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Antinociceptive and other behavioural effects of abnormal vestibular stimulation in the rat Gray, David Shaun 1981

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ANTINOCICEPTIVE AND OTHER BEHAVIOURAL EFFECTS OF ABNORMAL VESTIBULAR STIMULATION IN THE RAT by DAVID SHAUN GRAY B.Sc. The U n i v e r s i t y of C a l g a r y , 1975 M.Sc. The U n i v e r s i t y of C a l g a r y , 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of P h i l o s o p h y i n THE FACULTY OF GRADUATE STUDIES Department of P s y c h o l o g y We a c c e p t t h i s t h e s i s . a s c o n f o r m i n g to the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA March 1981 ©David Shaun Gray, 1981 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s thesis for s c h o l a r l y purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or p u b l i c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of PSYCHOLOGY The University of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date March 12, 1981 DE-6 (2/79) i i ABSTRACT Exposure t o abnormal motion produces a v a r i e t y of b e h a v i o u r a l e f f e c t s i n both human and non-human s p e c i e s . The g e n e r a l purpose of the p r e s e n t s t u d i e s was t o produce and i n v e s t i g a t e some of t h e s e e f f e c t s i n the l a b o r a t o r y r a t . In the f i r s t s e r i e s of e x p e r i m e n t s , r a t s d i s p l a y e d a p p r e c i a b l e d e c r e a s e s i n r e a c t i v i t y t o n o x i o u s s t i m u l i p r e s e n t e d a f t e r exposure t o b r i e f p e r i o d s of d i f f e r e n t t y p e s of motion. T h i s m o t i o n - i n d u c e d a n t i n o c i c e p t i o n was found t o p e r s i s t f o r p e r i o d s of up t o 15 min. A second s e r i e s of e x p e r i m e n t s examined the r o l e of the v e s t i b u l a r system i n t h i s m o t i o n - i n d u c e d a n t i n o c i c e p t i o n phenomenon. Rat s whose p e r i p h e r a l v e s t i b u l a r a p p a r a t u s had been r e n d e r e d i n s e n s i t i v e t o a c c e l e r a t i v e s t i m u l i d i d not e x h i b i t m o t i o n - i n d u c e d a n t i n o c i c e p t i o n . Subsequent e x p e r i m e n t s a t t e m p t e d t o d e l i n e a t e the r o l e of some i n d i v i d u a l components of the c e n t r a l v e s t i b u l a r system but no s i n g l e component i n v e s t i g a t e d was found t o p l a y a major r o l e i n the p r o d u c t i o n of a n t i n o c i c e p t i o n . E x p e r i m e n t s i n t h i s and the p r e c e d i n g s e r i e s of e x p e r i m e n t s a l s o demonstrated t h a t the a n t i n o c i c e p t i v e e f f e c t c o u l d be d i s s o c i a t e d from d i z z i n e s s or a c u t e v e s t i b u l a r d y s f u n c t i o n . In the t h i r d s e r i e s of e x p e r i m e n t s , the p h y s i o l o g i c a l mechanisms by which v e s t i b u l a r s t i m u l a t i o n produces a n t i n o c i c e p t i o n were i n v e s t i g a t e d . E x p e r i m e n t s i n t h i s s e r i e s d emonstrated t h a t m o t i o n - i n d u c e d a n t i n o c i c e p t i o n c o u l d be b l o c k e d by o p i a t e a n t a g o n i s t s and t h a t the m o t i o n - i n d u c e d a n t i n o c i c e p t i v e e f f e c t showed c r o s s - t o l e r a n c e w i t h c h r o n i c i i i morphine a d m i n i s t r a t i o n . These two f i n d i n g s s t r o n g l y i m p l i c a t e an endogenous o p i a t e p e p t i d e ( e n d o r p h i n ) sytem as the u n d e r l y i n g mechanism f o r mot i o n - i n d u c e d a n t i n o c i c e p t i o n . The b r i e f d u r a t i o n of the a n t i n o c i c e p t i v e e f f e c t and the f a c t t h a t d i s r u p t i o n of the p i t u i t a r y - a d r e n a l a x i s d i d not a f f e c t m o t i o n -induced a n t i n o c i c e p t i o n suggested t h a t the o p i a t e p e p t i d e s i n v o l v e d were the e n k e p h a l i n s r a t h e r than B-endorphin. Other b e h a v i o u r a l e f f e c t s of abnormal motion were r e p o r t e d i n the the f o u r t h s e r i e s of e x p e r i m e n t s . The resemblance between the symptoms of motion s i c k n e s s and those of o p i a t e a d m i n i s t r a t i o n s u g g ested t h a t endogenous o p i a t e p e p t i d e s may mediate motion s i c k n e s s . A l t h o u g h exposure t o abnormal motion d i d produce a s u b s t a n t i a l c o n d i t i o n e d t a s t e a v e r s i o n (a b e h a v i o u r a l assay f o r motion s i c k n e s s i n the r a t ) , a t t e m p t s t o a t t e n u a t e the a v e r s i o n w i t h two d i f f e r e n t o p i a t e a n t a g o n i s t s were u n s u c c e s s f u l . These r e s u l t s s u g g ested t h a t abnormal motion e x e r t s i t s i l l n e s s - p r o d u c i n g e f f e c t s t h r o u g h some mechanism o t h e r than an endogenous o p i a t e system. In the f i n a l e x p e r i m e n t , r a t s t h a t were exposed t o a b r i e f p e r i o d of abnormal motion s u b s e q u e n t l y e x h i b i t e d a s u p p r e s s i o n of d e f e n s i v e b u r y i n g b e h a v i o u r t h a t was s i m i l a r t o t h a t produced by a n x i o l y t i c d r u g s . The r e s u l t s of t h i s study i n d i c a t e t h a t abnormal v e s t i b u l a r s t i m u l a t i o n may have a v a r i e t y of d i f f e r e n t b e h a v i o u r a l e f f e c t s i n r a t s . However, i t appears t h a t no s i n g l e mechanism can account f o r a l l of t h e s e e f f e c t s . i v TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGEMENTS i x INTRODUCTION 1 B e h a v i o u r a l E f f e c t s of Abnormal V e s t i b u l a r S t i m u l a t i o n . 5 Mo t i o n S i c k n e s s 6 S i g n s and Symptoms 6 B i o c h e m i c a l Changes 9 S u s c e p t i b i l i t y t o M o t i o n S i c k n e s s 11 S o p o r i f i c and D r o w s i n e s s - I n d u c i n g P r o p e r t i e s of Abnormal M o t i o n 12 Calming or T r a n q u i l i z i n g E f f e c t s of Abnormal M o t i o n 13 A n t i n o c i c e p t i v e E f f e c t s of Abnormal M o t i o n 15 SECTION I - The A n t i n o c i c e p t i v e E f f e c t s of Abnormal M o t i o n 22 Experiment 1 23 Experiment 2 29 Experiment 3 38 Experiment 4 43 Experiment 5 48 G e n e r a l D i s c u s s i o n - S e c t i o n I 54 SECTION I I - V e s t i b u l a r M e d i a t i o n of the A n t i n o c i c e p t i v e Phenomenon 59 Experiment 6 60 V Experiment 7 69 Experiment 8 82 G e n e r a l D i s c u s s i o n - S e c t i o n I I 92 SECTION I I I - Mechanisms of M o t i o n - I n d u c e d A n a l g e s i a 96 Experiment 9 102 Experiment 10 108 Experiment 11 116 Experiment 12 128 G e n e r a l D i s c u s s i o n - S e c t i o n I I I 137 SECTION IV - Other B e h a v i o u r a l E f f e c t s of Abnormal M o t i o n . 140 Experiment 13 141 Experiment 14 155 Experiment 15 163 GENERAL DISCUSSION 177 Mo t i o n - I n d u c e d A n t i n o c i c e p t i o n 180 P h y s i o l o g i c a l Mechanisms of M o t i o n - I n d u c e d A n t i n o c i c e p t i o n 180 S t r e s s - I n d u c e d and M o t i o n - I n d u c e d A n a l g e s i a . 183 Endogenous O p i a t e Mechanisms 184 Non-Opiate Mechanisms 185 A p p l i c a t i o n s of the M o t i o n - I n d u c e d A n a l g e s i a Phenomenon 188 M o t i o n S i c k n e s s 191 Calming E f f e c t s of Abnormal M o t i o n 195 C o n c l u s i o n s 198 REFERENCES 201 v i LIST OF TABLES 1. Comparison of some s i g n s and symptoms e l i c i t e d by o p i a t e (morphine) a d m i n i s t r a t i o n and by exposure t o abnormal motion 144 v i i LIST OF FIGURES 1. Mean t a i l movement and t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed t o b r i e f p e r i o d s of motion or r e s t r a i n t 18 2. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed t o r e s t r a i n t or t o one of two d i f f e r e n t motion c o n d i t i o n s i n Experiment 1 28 3. Schematic r e p r e s e n t a t i o n of the motion d e v i c e used i n Experiment 2 33 4. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s i n Experiment 2 36 5. Mean b a l a n c e beam s c o r e s f o r r a t s t e s t e d i n one of the f o u r d i f f e r e n t motion c o n d i t i o n s i n Experiment 3 41 6. R e s u l t s of a n a l g e s i a t e s t i n g i n Experiment 4 47 7. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed t o 5-, 30-, 300-, or 900-sec p e r i o d s of the motion t r e a t m e n t used i n Experiment 5 51 8. E f f e c t s of p e r i p h e r a l v e s t i b u l a r a p p a r a t u s l e s i o n s on t a i l w i t h d r a w a l l a t e n c i e s i n Experiment 6 66 9. R e s u l t s of v e s t i b u l a r d y s f u n c t i o n t e s t s i n Experiment 6 68 10. H i s t o l o g i c a l r e s u l t s f o r Experiment 7 74 11. R e s u l t s of Experiment 7 d e p i c t i n g the e f f e c t s of abnormal motion on t a i l w i t h d r a w a l l a t e n c i e s i n the MVN, LVN, and CER l e s i o n groups 77 12. E f f e c t s of motion and r e s t r a i n t on b a l a n c e beam v i i i s c o r e s i n the MVN, LVN, CER, and SHAM l e s i o n groups of Experiment 7 79 13. L o c a t i o n s of the s t i m u l a t i n g e l e c t r o d e s i n Experiment 8 86 14. E f f e c t s of e l e c t r i c a l s t i m u l a t i o n i n the MVN, LVN, and CER on t a i l w i t h d r a w a l l a t e n c i e s i n Experiment 8 89 15. E f f e c t s of v a r i o u s doses of naloxone on the m o t i o n - i n d u c e d a n a l g e s i a phenomenon. 106 16. D i f f e r e n t i a l e f f e c t s of naloxone on m o t i o n , r e s t r a i n t , and c o l d - w a t e r swim t r e a t m e n t s i n Experiment 10 I l l 17. Mean b a l a n c e s c o r e s f o r r a t s r e c e i v i n g s a l i n e or naloxone i n the motion and r e s t r a i n t c o n d i t i o n s of Experiment 10 115 18. E f f e c t s of c h r o n i c morphine, m o t i o n , s a l i n e , or r e s t r a i n t t r e a t m e n t s i n Experiment 11 121 19. R e s u l t s of the acu t e t e s t phase of Experiment 11 124 20. E f f e c t s of adrenalectomy on m o t i o n - i n d u c e d a n a l g e s i a 135 21. Mean s a c c h a r i n p r e f e r e n c e b e f o r e and a f t e r p a i r i n g w i t h abnormal motion 152 22. Mean s a c c h a r i n p r e f e r e n c e a f t e r p a i r i n g of s a c c h a r i n and motion i n r a t s p r e t r e a t e d w i t h n a l t r e x o n e 159 23. E f f e c t s of b r i e f p r e e x p o s u r e t o motion or shock on d e f e n s i v e b u r y i n g b e h a v i o u r 170 i x ACKNOWLEDGEMENTS The a u t h o r wishes t o thank Dr. B.B. G o r z a l k a f o r h i s a s s i s t a n c e and encouragement as s u p e r v i s o r of the a u t h o r ' s d i s s e r t a t i o n program. The a s s i s t a n c e of the r e m a i n i n g members of the t h e s i s committee, D r s . J . P . J . P i n e l and K. C r a i g i s a l s o g r a t e f u l l y acknowledged. The a u t h o r a l s o wishes t o acknowledge the c o n t r i b u t i o n s of a number of o t h e r people t o t h i s t h e s i s : L o r i J . T e r l e c k i f o r her a s s i s t a n c e and encouragement, Sandra K l e i n f e l d f o r her i n v a l u a b l e t e c h n i c a l s u p p o r t , and H. Umedaly f o r a s s i s t a n c e i n p e r f o r m i n g e x p e r i m e n t s 1 and 9. T h i s r e s e a r c h was pursued d u r i n g the a u t h o r ' s t e n u r e of a N a t u r a l S c i e n c e s and E n g i n e e r i n g R e s e a r c h C o u n c i l p o s t - g r a d u a t e s c h o l a r s h i p and a U n i v e r s i t y of B r i t i s h Columbia p o s t - g r a d u a t e s c h o l a r s h i p and was s u p p o r t e d by a N a t u r a l S c i e n c e s and E n g i n e e r i n g Research C o u n c i l o p e r a t i n g g r a n t and a P r o v i n c e of B r i t i s h Columbia Youth Employment g r a n t . 1 INTRODUCTION The v e s t i b u l a r system i s an i m p o r t a n t and h i g h l y complex se n s o r y system t h a t e x i s t s i n some form i n many a n i m a l s p e c i e s ( B a l o h & H o n r u b i a , 1979; B r o d a l & Pompeiano, 1972; B r o d a l , Pompeiano, & Walberg, 1962; C l a r k , 1970; Kornhuber, 1974; Naunton,1975). T h i s system i s h i g h l y s p e c i a l i z e d f o r the d e t e c t i o n and c e n t r a l nervous system i n t e g r a t i o n of a c c e l e r a t i v e movements of the head t h a t a r e e i t h e r g e n e r a t e d by the organism or p a s s i v e l y e x p e r i e n c e d ( B a l o h & H o n r u b i a , 1979; G o l d s t e i n , 1974). T h i s s p e c i a l i z e d c a p a c i t y f o r the d e t e c t i o n of motion and head movement i s i n t r i n s i c t o the r o l e of the v e s t i b u l a r system i n p o s t u r e and s p a t i a l o r i e n t a t i o n . A l t h o u g h the anatomy and n e u r o p h y s i o l o g y of the v e s t i b u l a r system have been w e l l s t u d i e d w i t h r e s p e c t t o p o s t u r a l and o r i e n t i n g r e f l e x e s (see Howard & Templeton, 1966; Pa r k e r , 1 9 8 0 ; R o b e r t s , 1967), the in v o l v e m e n t of the v e s t i b u l a r system i n o t h e r forms of b e h a v i o u r has been l a r g e l y i g n o r e d by p s y c h o l o g i s t s and b e h a v i o u r a l neurosc i e n t i s t s . One d i f f i c u l t y i n s t u d y i n g the r o l e of the v e s t i b u l a r system i n b e h a v i o u r l i e s i n the n a t u r e of normal v e s t i b u l a r f u n c t i o n i n g . The v e s t i b u l a r system i s unique among se n s o r y systems i n t h a t i t i s e s s e n t i a l y ' s i l e n t ' i n the c o u r s e of i t s normal f u n c t i o n i n g (Reason & Brand, 1975, p. 8 5 ) . That i s , v e s t i b u l a r f u n c t i o n i n g does not e n t e r c o n s c i o u s n e s s i n the same manner as do v i s u a l , a u d i t o r y , g u s t a t o r y , or t a c t i l e s e n s a t i o n s . The u n o b t r u s i v e n a t u r e of the v e s t i b u l a r system means t h a t any b e h a v i o u r a l consequences of v e s t i b u l a r a c t i v i t y a r e o b v i o u s o n l y when some degree of abnormal v e s t i b u l a r a c t i v a t i o n e x i s t s . One 2 way t h i s abnormal a c t i v i t y may be generated i s by exposure to abnormal acceleration (Clark, 1970; Parker,1980; Reason & Brand, 1975), i . e . acceleration that would not t y p i c a l l y be generated by the organism in the course of i t s normal motor a c t i v i t y . The study of the role of the vestibular system in behaviour then, r e l i e s to a great extent on the study of the behavioural consequences of exposure to abnormal motion although abnormal vestibular a c t i v i t y may also be induced pharmacologically (Money & Myles, 1974), or by disease (Hood, 1978). There are a number of r e l i a b l e behavioural e f f e c t s that result from exposure of an organism to abnormal motion. These behavioural consequences include: nausea, vomiting, and a number of related symptoms (motion sickness); depression and dysphoria in humans; and a s o p o r i f i c or t r a n q u i l i z i n g e f f e c t . Although some aspects of some of these behavioural consequences of exposure to abnormal motion have been well studied (e.g. motion sickness), the study of the behavioural consequences of exposure to abnormal motion has, to the surprise of some authors (e.g. Clark, 1970; Money, 1970; Reason & Brand, 1975), received l i t t l e attention. Not only i s there a paucity of information concerning these behavioural consequences, l i t t l e information exists concerning the physiological mechanisms that mediate these behavioural consequences. Even motion sickness, perhaps the best known consequence of abnormal vestibular stimulation, is poorly understood in terms of i t s physiological mechanisms (Money, 1970; Reason & Brand, 1975). A previously unexplored behavioural consequence of abnormal motion has recently been investigated by Gray (unpublished data, 3 1979). F o l l o w i n g b r i e f p e r i o d s of abnormal v e s t i b u l a r s t i m u l a t i o n , i t appears t h a t t h e r e i s an a t t e n u a t i o n of r e s p o n s i v e n e s s t o n o x i o u s or p a i n f u l s t i m u l i . T h i s e f f e c t has not been e x t e n s i v e l y s t u d i e d and i s d e s c r i b e d i n more d e t a i l below. Study of t h i s a n t i n o c i c e p t i v e e f f e c t of abnormal motion c o u l d p o s s i b l y p r o v i d e some i n d i c a t i o n of the mechanisms u n d e r l y i n g the p e r c e p t i o n of p a i n . The purpose of the p r e s e n t t h e s i s was t o i n v e s t i g a t e some of the b e h a v i o u r a l e f f e c t s of abnormal motion and the p o s s i b l e p h y s i o l o g i c a l mechanisms r e s p o n s i b l e f o r t h e s e e f f e c t s . P a r t i c u l a r emphasis was p l a c e d on the n a t u r e of the a n t i n o c i c e p t i v e e f f e c t d e s c r i b e d above and the p h y s i o l o g i c a l mechanisms u n d e r l y i n g i t . A l t h o u g h the b e h a v i o u r a l e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n have not been e x t e n s i v e l y s t u d i e d i n the p a s t , t h e i r s tudy would seem t o w a r r a n t a t t e n t i o n f o r a v a r i e t y of r e a s o n s . One c o m p e l l i n g r a t i o n a l e f o r t h e i r i n v e s t i g a t i o n i s of an a p p l i e d n a t u r e . For example, as s o c i e t y advances i n t r a n s p o r t t e c h n o l o g y , the o p e r a t o r s and p a s s e n g e r s of t h e s e v e h i c l e s a r e exposed t o a g r e a t number of abnormal f o r c e s . An u n d e r s t a n d i n g of the consequences of exposure t o these abnormal f o r c e s would seem e s s e n t i a l t o the s a f e t y and s u c c e s s of t h e s e o p e r a t i o n s . M o t i o n s i c k n e s s ( a i r s i c k n e s s , space s i c k n e s s , sea s i c k n e s s ) , f o r example, i s an e x t r e m e l y common response t o exposure t o abnormal f o r c e s (Johnson & Jongkees, 1974; Money, 1970; Reason & Brand, 1975). As w i l l be d i s c u s s e d i n g r e a t e r d e t a i l below, motion s i c k n e s s r e p r e s e n t s a c o n s t e l l a t i o n of b e h a v i o u r a l e f f e c t s i n c l u d i n g nausea, v o m i t i n g , d r o w s i n e s s , 4 d e p r e s s i o n and d y s p h o r i a , c o l d s w e a t i n g , p a l l o r , and v a r i o u s o t h e r b e h a v i o u r a l and p h y s i o l o g i c a l r e a c t i o n s (Johnson & Jongkees, 1974; Money, 1970; Reason & Brand, 1975). A l t h o u g h perhaps not a l i f e t h r e a t e n i n g d i s o r d e r i n i t s e l f , i t i s c l e a r t h a t motion s i c k n e s s c o u l d w e l l a f f e c t the o p t i m a l performance of s u b j e c t s e x h i b i t i n g t h i s syndrome. For example, a number of m i s s i o n s i n space have been c o m p l i c a t e d by the motion s i c k n e s s of the f l i g h t crew (see G r a y b i e l , 1980; Reason & Brand, 1975; S c h n e i d e r & Crosb y , 1980). The p o s s i b i l i t y of i m p a i r e d performance r e s u l t i n g from exposure t o abnormal f o r c e s has o b v i o u s i m p l i c a t i o n s i n both m i l i t a r y and c i v i l i a n o p e r a t i o n s such as t r o o p t r a n s p o r t , f l i g h t s a f e t y , e t c . A second reason f o r i n t e r e s t i n the b e h a v i o u r a l e f f e c t s of v e s t i b u l a r a c t i v a t i o n c o n c e r n s the p o s s i b l e m e d i a t i o n of the e f f e c t s of drugs and t o x i c s u b s t a n c e s by the v e s t i b u l a r system. G u t n e r , G o u l d , and Batterman (1952) and Money (1970), f o r example, have suggested t h a t t h e r e i s a s y n e r g i s t i c e f f e c t of a t l e a s t some drug t r e a t m e n t s and v e s t i b u l a r a c t i v i t y i n p r o d u c i n g some of the advers e s i d e e f f e c t s of t h e s e d r u g s . The nausea and v o m i t i n g produced by morphine (Gutner e t a l . , 1952; J a f f e & M a r t i n , 1975) or apomorphine (Money, 1970) a r e much l e s s e v i d e n t i n p a t i e n t s who remain m o t i o n l e s s than i n p a t i e n t s who are a m b u l a t o r y . Treisman (1977) has r e c e n t l y suggested t h a t motion s i c k n e s s i s a c t u a l l y a h i g h l y a d a p t i v e mechanism f o r the d e t e c t i o n , e l i m i n a t i o n , and subsequent a v o i d a n c e of n a t u r a l l y o c c u r r i n g t o x i c s u b s t a n c e s . A c c o r d i n g t o t h i s h y p o t h e s i s , t o x i c s u b s t a n c e s can d i s r u p t the u s u a l congruence between the senses used i n s p a t i a l o r i e n t a t i o n ( i . e . the v e s t i b u l a r , v i s u a l , and 5 p r o p r i o c e p t i v e systems) t o produce a s i t u a t i o n t h a t resembles the e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n . One of the s e e f f e c t s i s v o m i t i n g , a b e h a v i o u r t h a t may ha s t e n the e l i m i n a t i o n of any r e m a i n i n g t o x i c s u b s t a n c e . V o m i t i n g produced by a t o x i c s u bstance may cause an organism t o a v o i d t h a t s u b s t a n c e i n the f u t u r e ; i . e . i t may e s t a b l i s h a c o n d i t i o n e d t a s t e a v e r s i o n (see G a r c i a & H a n k i n s , 1977; Gustavson, 1977). A l t h o u g h the e x a c t n a t u r e of the i n t e r a c t i o n between drugs and the v e s t i b u l a r system i s not known, i t i s c l e a r t h a t a t l e a s t some drugs e x e r t some of t h e i r e f f e c t s by a d i r e c t a c t i o n on the v e s t i b u l a r system. Money and M y l e s (1974) f o r example, have found t h a t a l c o h o l produces the well-known p o s i t i o n a l a l c o h o l nystagmus (PAN) e f f e c t t h r o u g h a d i r e c t a c t i o n on the c u p u l a of the l a b y r i n t h i n e c a n a l s . PAN i s a r e p e t i t i v e c y c l e of slow d r i f t i n g eye movements i n one d i r e c t i o n f o l l o w e d by a r a p i d r e t u r n i n the o p p o s i t e d i r e c t i o n , the d i r e c t i o n s of the slow and f a s t phases b e i n g dependent on head p o s i t i o n a f t e r i n g e s t i o n of a moderate amount of a l c o h o l . T h i s e f f e c t appears t o r e l y more on the p h y s i c a l p r o p e r t i e s of the drug ( i . e . d e n s i t y ) than on a d i r e c t p h a r m a c o l o g i c a l e f f e c t , but n o n e t h e l e s s i l l u s t r a t e s t h a t drugs can and do e x e r t some of t h e i r e f f e c t s t h r o u g h v e s t i b u l a r mechanisms. Many drugs produce nausea, d i z z i n e s s , and v o m i t i n g (see Goodman & G i l m a n , 1975; Ro t e n b e r g , 1978), and the v e s t i b u l a r system may prove t o p l a y an i m p o r t a n t r o l e i n t h e i r e t i o l o g y . BEHAVIOURAL EFFECTS OF ABNORMAL VESTIBULAR STIMULATION From a s u r v e y of the l i t e r a t u r e , i t appears t h a t t h e r e a r e a t l e a s t t h r e e k i n d s of b e h a v i o u r a l e f f e c t s of abnormal m o t i o n . 6 These i n c l u d e : i l l n e s s i n d u ced by motion (motion s i c k n e s s ) , a s o p o r i f i c or s l e e p i n d u c i n g e f f e c t , and a c a l m i n g or a n x i o l y t i c e f f e c t . In a d d i t i o n , r e c e n t s t u d i e s i n our own l a b o r a t o r y have suggested t h a t exposure t o abnormal motion can a l s o have a n t i n o c i c e p t i v e e f f e c t s . The purpose of the f o l l o w i n g r e v i e w i s t o d e s c r i b e t h e s e b e h a v i o u r a l e f f e c t s i n g r e a t e r d e t a i l . A l t h o u g h i t may seem t h a t a d i s p r o p o r t i o n a t e amount of d i s c u s s i o n i s dev o t e d t o motion s i c k n e s s , i t s h o u l d be noted t h a t t h i s d i s p r o p o r t i o n a l i t y s i m p l y r e f l e c t s the e x t e n t of the r e l e v a n t l i t e r a t u r e . M o t i o n S i c k n e s s M o t i o n s i c k n e s s i s perhaps the b e s t known e f f e c t of abnormal v e s t i b u l a r a c t i v i t y . T h i s d i s o r d e r has been known i n humans s i n c e the time of the a n c i e n t Greeks as sea s i c k n e s s (Reason & Brand, 1975) and has r e c e n t l y become of g r e a t i n t e r e s t because of r e c e n t advances i n a i r and space t r a v e l . The term motion s i c k n e s s r e f e r s t o i l l n e s s produced by exposure t o abnormal f o r c e environments t h a t r e s u l t s i n a c o n f l i c t between (Reason, 1978) or an attempt t o r e i n t e g r a t e (Treisman, 1977) i n f o r m a t i o n from v a r i o u s senses p r o v i d i n g s p a t i a l i n f o r m a t i o n ( e . g . , cinerama s i c k n e s s , s i m u l a t o r s i c k n e s s ) . M o t i o n s i c k n e s s i s not a u n i t a r y phenomenon and a c t u a l l y r e p r e s e n t s a wide v a r i e t y of symptoms and s i g n s produced as a r e s u l t of exposure t o abnormal v e s t i b u l a r a c t i v i t y . The most o b v i o u s and r e l i a b l e of t h e s e a r e d i s c u s s e d below. S i g n s and symptoms Nausea and v o m i t i n g . Nausea ( t h e f e e l i n g of impending emesis) and v o m i t i n g ( t h e a c t u a l a c t of emesis) a r e u s u a l l y 7 c o n s i d e r e d as the e n d p o i n t or most s e v e r e symptoms of the motion s i c k n e s s syndrome (Money, 1970; Reason & Brand, 1975). V o m i t i n g i s not an i n e v i t a b l e consequence of nausea. In e x p e r i m e n t a l l y produced motion s i c k n e s s , i t i s p o s s i b l e t o a d j u s t the s t i m u l u s c o n d i t i o n s so t h a t v o m i t i n g does not o c c u r , even though s u b j e c t s r e p o r t nausea t o be p r e s e n t (Kennedy & G r a y b i e l , 1965). The nausea and v o m i t i n g seen i n motion s i c k n e s s i s i n d i s t i n g u i s h a b l e from nausea and v o m i t i n g produced as a r e s u l t of the a p p l i c a t i o n of o t h e r emetic agents (Money, 1970; Reason & Brand, 1975). I f the a r e a postrema, a s e n s i t i v e " t r i g g e r zone" f o r emesis, i s removed from the b r a i n s t e m of an e x p e r i m e n t a l a n i m a l , t h a t a n i m a l i s r e n d e r e d i n s e n s i t i v e t o v o m i t i n g produced both by c e n t r a l l y a c t i n g emetic drugs (Wang & B o r i s o n , 1952) and by motion ( B r i z z e e , Ordy, & M e h l e r , 1980; Money, 1970). Emetic a g e n t s , such as copper s u l f a t e , t h a t a r e thought t o e x e r t t h e i r e metic a c t i o n s p e r i p h e r a l l y , such as copper s u l f a t e , a r e s t i l l e f f e c t i v e i n i n d u c i n g emesis i n such an a n i m a l (Wang, 1965). T h i s f a c t s u g g e s t s t h a t abnormal motion e x e r t s i t s emetic a c t i o n s t h r o u g h some mechanism i n the c e n t r a l nervous system r a t h e r than t h r o u g h a p e r i p h e r a l mechanism. The e x a c t n a t u r e of t h i s c e n t r a l mechanism however, remains unknown. P a l l o r and c o l d s w e a t i n g . In a d d i t i o n t o nausea and v o m i t i n g , the two most commonly o b s e r v e d symptoms of motion s i c k n e s s a r e p a l l o r , the r e s u l t of v a s o c o n s t r i c t i o n of the s k i n , and c o l d s w e a t i n g , which i s p e r s p i r a t i o n i n the absence of an adequate t h e r m a l s t i m u l u s . A l t h o u g h t h e s e symptoms can r e s u l t from a c t i v a t i o n of the autonomic nervous system, Money (1970) has suggested t h a t autonomic nervous system a c t i v a t i o n i s not 8 n e c e s s a r i l y the cause of p a l l o r and c o l d s w e a t i n g i n motion s i c k n e s s but t h a t p a l l o r and c o l d s w e a t i n g may be the r e s u l t of the l i b e r a t i o n of some o t h e r c i r c u l a t i n g c h e m i c a l . I t s h o u l d be remembered t h a t a l t h o u g h p a l l o r and c o l d s w e a t i n g o f t e n occur d u r i n g motion s i c k n e s s , t h e i r p r e s e n c e a l o n e i s not s u f f i c i e n t t o j u s t i f y a d i a g n o s i s of motion s i c k n e s s . A n x i e t y , f o r example, i s s u f f i c i e n t t o provoke p a l l o r and c o l d "sweating i n the absence of unusual motion (Reason & Brand, 1975, p. 4 4 ) . D e p r e s s i o n and d y s p h o r i a . M o t i o n s i c k n e s s i s accompanied by p r o f o u n d d y s p h o r i a and a v e r y s e v e r e s t a t e of d e p r e s s i o n , apathy, and l e t h a r g y i n some i n d i v i d u a l s (Money, 1970; Reason & Brand, 1975). The degree of d e p r e s s i o n appears t o be c o m p l e t e l y a t odds w i t h the a c t u a l s e r i o u s n e s s of the malady, and p e r s o n s s u f f e r i n g from motion s i c k n e s s have o f t e n been noted t o w i s h f o r d e a t h (see Reason & Brand, 1975). T h i s d e p r e s s i o n can be so severe t h a t Money (1970) has s u g g e s t e d t h a t the mechanisms i n v o l v e d i n t h i s form of a c u t e d e p r e s s i o n may a l s o be i n v o l v e d i n o t h e r forms of p a t h o l o g i c a l d e p r e s s i o n . However, d e s p i t e i t s s i g n i f i c a n c e , r e p o r t s of m o t i o n - i n d u c e d d e p r e s s i o n have been a n e c d o t a l ; l i t t l e or no s y s t e m a t i c e v i d e n c e e x i s t s c o n c e r n i n g i t s n a t u r e . A d d i t i o n a l s i g n s and symptoms. There a r e a number of o t h e r s i g n s and symptoms t h a t may o c c a s i o n a l l y r e s u l t from exposure t o abnormal motion c o n d i t i o n s . I n c r e a s e d s a l i v a t i o n i s f r e q u e n t l y noted i n c o n j u n c t i o n w i t h nausea i n both humans and o t h e r a n i m a l s (Money, 1970; Reason & Brand, 1975). In humans, i n c r e a s e d s a l i v a t i o n i s 9 i n f e r r e d by more f r e q u e n t s w a l l o w i n g whereas i n o t h e r a n i m a l s s a l i v a may be e v i d e n t d r i p p i n g from the mouth. An i n c r e a s e i n r e s p i r a t i o n r a t e independent of the presence of o t h e r symptoms i s sometimes noted (Reason & Brand, 1975), and p a n t i n g f r e q u e n t l y accompanies motion s i c k n e s s i n c a n i n e s ( B a b k i n , Dworkin, & S c h a c t e r , 1966). F o l l o w i n g p r o l o n g e d exposure t o abnormal m o t i o n , c o n s t i p a t i o n and l o s s of g a s t r o - i n t e s t i n a l tone a r e f r e q u e n t l y found, p r i m a r i l y i n humans (Reason & Brand, 1975). In a d d i t i o n t o d e c r e a s e d g a s t r o i n t e s t i n a l t o n e , a s u p p r e s s i o n of u r i n a r y o u t p u t has a l s o been noted ( G r a y b i e l , Kennedy, K n o b l o c k , Guedry, H e r t z , McCleod, C o l e h u r , M i l l e r , & F r e g l y , 1965). F r o n t a l headache i s a n o t h e r commonly r e p o r t e d symptom d u r i n g the e a r l y s t a g e s of motion s i c k n e s s , p a r t i c u l a r l y i n s i t u a t i o n s where the p r o v o c a t i v e s t i m u l u s i n v o l v e s c r o s s - c o u p l e d a n g u l a r a c c e l e r a t i o n s (Reason & Brand, 1975). Other symptoms i n c l u d e a n o r e x i a , mental c o n f u s i o n , f e e l i n g s of c o l d n e s s i n the f a c e and e x t r e m i t i e s , and a f e e l i n g of i n c r e a s e d o v e r a l l b o d i l y warmth (Reason & Brand, 1975). A few a u t h o r s ( e . g . , C h i n n , N o e l l , & S m i t h , 1950) have noted t h a t the development of s e a s i c k n e s s was a s s o c i a t e d w i t h e l e c t r o e n c e p h a l o g r a p h i c changes. An a c t i v a t i o n of the a l p h a rhythm and a s l o w i n g of the dominant wave f r e q u e n c y were found i n c a s e s of p e r s i s t e n t or c h r o n i c motion s i c k n e s s . B i o c h e m i c a l changes. There a r e a l s o a number of b i o c h e m i c a l and hormonal changes t h a t r e s u l t from exposure t o abnormal motion e n v i r o n m e n t s . D u r i n g p r o l o n g e d ( i . e . , 12 day) exposure t o abnormal 10 v e s t i b u l a r s t i m u l a t i o n i n human s u b j e c t s , d e c r e a s e s i n g l u c o s e u t i l i z a t i o n on the f i r s t day of r o t a t i o n were found, f o l l o w e d on subsequent days by a g r e a t l y i n c r e a s e d g l u c o s e u t i l i z a t i o n r a t e ( G r a y b i e l e t a l . , 1965). L a c t i c a c i d dehydrogenase c o n c e n t r a t i o n s i n b l o o d were found t o f o l l o w a p a t t e r n s i m i l a r t o t h a t found f o r g l u c o s e u t i l i z a t i o n . In s e v e r a l s t u d i e s , l e v e l s of hormones t y p i c a l l y r e l e a s e d i n response t o s t r e s s f u l s t i m u l a t i o n were found t o be e l e v a t e d f o l l o w i n g exposure t o abnormal m o t i o n . I n c r e a s e d s e c r e t i o n of a d r e n a l c o r t i c o s t e r o i d s ( e . g . , C o r t i s o l ) and t h e i r m e t a b o l i c p r o d u c t s has been found t o r e s u l t from abnormal v e s t i b u l a r a c t i v i t y i n b o t h humans (Eversmann, Gottsman, U h l i c h , U l b r e c h t , von Worden, & S c r i b a , 1978) and o t h e r a n i m a l s (Fox, K i e l , Daunton, Thomsom, D i c t o r , & Chee, 1980). In a d d i t i o n , i n c r e a s e d s e c r e t i o n of the a d r e n a l c a t e c h o l a m i n e s , e p i n e p h r i n e and n o r e p i n e p h r i n e , has a l s o been n o t e d ( C o l e h o u r , 1965; Money, 1970; Reason & Brand, 1975). None of these changes was observed i n s u b j e c t s w i t h i m p a i r e d v e s t i b u l a r s e n s i t i v i t y , s u g g e s t i n g t h a t t h e s e hormonal e f f e c t s depended on the i n t e g r i t y of the v e s t i b u l a r system. These hormonal and b i o c h e m i c a l changes suggest t h a t abnormal motion may a c t as a s t r e s s o r . A s t r e s s o r i s u s u a l l y d e f i n e d i n terms of an a c t i v a t i o n of the p i t u i t a r y - a d r e n a l a x i s ( L e s h n e r , 1979; S e l y e , 1956). I n c r e a s e d s e c r e t i o n of a d r e n o c o r t i c o t r o p h i c hormone (ACTH) from the a n t e r i o r p i t u i t a r y r e s u l t s i n the i n c r e a s e d s e c r e t i o n of s t e r o i d s from the a d r e n a l c o r t i c e s whereas a d r e n a l m e d u l l a r y c a t e c h o l a m i n e s a r e s e c r e t e d i n response t o a c t i v a t i o n of the p a r a s y m p a t h e t i c d i v i s i o n of the 11 autonomic nervous system (Mason, 1968). The d e c r e a s e d u r i n e p r o d u c t i o n found d u r i n g motion s i c k n e s s i s thought t o r e s u l t from an i n c r e a s e d output of a n t i d i u r e t i c hormone (ADH). ADH, a l s o known as v a s o p r e s s i n , i s r e l e a s e d from the p o s t e r i o r p i t u i t a r y and a c t s t o decrease u r i n a r y output ( L e v i n e , 1972). S u s c e p t i b i l i t y t o motion s i c k n e s s A l t h o u g h i n d i v i d u a l s u s c e p t i b i l i t y t o motion s i c k n e s s v a r i e s , i t has been suggested t h a t almost any s u b j e c t may be made motion s i c k g i v e n the a p p r o p r i a t e s t i m u l u s c o n d i t i o n s (Reason & Brand, 1975). I t a p p e a r s , however, t h a t the v e s t i b u l a r system i s a n e c e s s a r y c o n d i t i o n f o r the o c c u r r e n c e of motion s i c k n e s s ; i t i s d i f f i c u l t , i f not i m p o s s i b l e , t o induce motion s i c k n e s s i n s u b j e c t s w i t h s e v e r e l y d e f e c t i v e v e s t i b u l a r systems ( G r a y b i e l , 1965; Money & F r i e d b e r g , 1964). A wide v a r i e t y of s p e c i e s i n c l u d i n g dogs, c a t s , h o r s e s , sheep, monkeys, s e a l s , b i r d s , cows, and even c o d f i s h have been r e p o r t e d t o be s u s c e p t i b l e (Money, 1970). M o t i o n s i c k n e s s has a l s o been r e p o r t e d t o e x i s t i n the r a t , a s p e c i e s t h a t does not vomit ( C o i l & G a r c i a , 1977; Hatcher & Weiss, 1923). Because the r a t does not e x h i b i t e m e s i s , the most o b v i o u s and r e l i a b l e s i g n of motion s i c k n e s s , o t h e r t e c h i q u e s have been u t i l i z e d as a s s a y s of m o t i o n - i n d u c e d i l l n e s s i n t h i s s p e c i e s . These t e c h n i q u e s i n c l u d e the f o r m a t i o n of c o n d i t i o n e d t a s t e a v e r s i o n s t o n o v e l f l a v o u r s f o l l o w i n g a p e r i o d of abnormal motion (Green & R a c h l i n , 1973, 1976; H a r o u t u n i a n & R i c c i o , 1975; R i c c i o & H a r o u t u n i a n , 1976; Roy & B r i z z e e , 1979), an i n c r e a s e d w i l l i n g n e s s t o consume a n o n - n u t r i t i v e c l a y or s o i l m i x t u r e 12 ( p i c a or geophagia) f o l l o w i n g abnormal motion ( M i t c h e l l , Krusemark, & H a f n e r , 1977; M i t c h e l l , Laycock, & Stephens, 1977), s u p p r e s s i o n of d r i n k i n g f o l l o w i n g abnormal motion ( H a r o u t u n i a n , R i c c i o , & Gans, 1976), and d e c r e a s e d motor a c t i v i t y d u r i n g the p e r i o d of abnormal motion ( E s k i n & R i c c i o , 1966; R i c c i o & Thach, 1968). A l t h o u g h these s t u d i e s would seem t o suggest t h a t abnormal motion i s a v e r s i v e f o r the r a t , i t i s not as o b v i o u s t h a t a l l of the b e h a v i o u r s a f f e c t e d by abnormal motion are s i g n s of motion s i c k n e s s . However, th e s e s t u d i e s and o t h e r s ( e . g . , Weissman & G o t t l i e b , 1969) do c l e a r l y demonstrate t h a t r a t s a r e s e n s i t i v e t o abnormal motion and abnormal v e s t i b u l a r a c t i v i t y . I t s h o u l d be noted t h a t t h i s r e v iew does not do j u s t i c e t o the e x t e n s i v e body of l i t e r a t u r e on motion s i c k n e s s ( e . g . , see Johnson & Jongkees, 1974; Money, 1970; Reason & Brand, 1975). I t does however, i l l u s t r a t e t h a t t h e r e do e x i s t a number of r e l i a b l e and q u a n t i f i a b l e e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n t h a t may be s t u d i e d i n a l a b o r a t o r y s i t u a t i o n . S o p o r i f i c and Drowsiness I n d u c i n g P r o p e r t i e s , o f Abnormal M o t i o n Drowsiness and s l e e p i n s i t u a t i o n s t h a t induce motion s i c k n e s s have been r e p o r t e d i n a number of i n v e s t i g a t i o n s i n v o l v i n g b o t h s h o r t ( S u r i , Crampton, & Daunton, 1979) and l o n g -term (Reason & G r a y b i e l , 1971) exposure of humans ( G r a y b i e l & Knepton, 1976) and o t h e r s p e c i e s (Ordy & B r i z z e e , 1980; S u r i e t a l . , 1979) t o abnormal m o t i o n . F u r t h e r m o r e , Chinn e t a l . (1950) found e l e c t r o e n c e p h a l o g r a p h i c p a t t e r n s i n s e a s i c k i n d i v i d u a l s t h a t were s u g g e s t i v e of d r o w s i n e s s . A l t h o u g h the s l e e p - i n d u c i n g e f f e c t of abnormal v e s t i b u l a r a c t i v i t y i s o f t e n found i n c o n j u n c t i o n w i t h the appearance of 13 motion s i c k n e s s , the s l e e p - i n d u c i n g and i l l n e s s - i n d u c i n g p r o p e r t i e s of v e s t i b u l a r s t i m u l a t i o n appear t o r e p r e s e n t two d i s t i n c t phenomena. G r a y b i e l and Knepton (1976) have i n f a c t d e s c r i b e d the d r o w s i n e s s - i n d u c i n g e f f e c t of abnormal motion as a d i s t i n c t syndrome: the S o p i t e syndrome. D r o w s i n e s s i s o f t e n found i n s u b j e c t s t h a t a r e o t h e r w i s e c o m p l e t e l y u n a f f e c t e d ( G r a y b i e l & Knepton, 1976). F u r t h e r m o r e , the s l e e p - i n d u c i n g e f f e c t of abnormal motion o f t e n p e r s i s t s , even a f t e r the o t h e r i l l n e s s - i n d u c i n g e f f e c t s of abnormal motion have d i s a p p e a r e d t h r o u g h a d a p t a t i o n t o the c o n t i n u i n g s t i m u l u s (Reason & Brand, 1975). Recent e v i d e n c e s u g g e s t s t h a t abnormal v e s t i b u l a r s t i m u l a t i o n i s a l s o e x t r e m e l y e f f e c t i v e i n i n d u c i n g s l e e p i n human i n f a n t s (Pederson & Ter V r u g t , 1973; Ter V r u g t & Pederson, 1973) T h i s i s p a r t i c u l a r l y i n t e r e s t i n g i n view of the f a c t t h a t i n f a n t s a r e g e n e r a l l y r e p o r t e d t o be immune t o the i l l n e s s -i n d u c i n g p r o p e r t i e s of abnormal motion (Reason & Brand, 1975). I t would seem t h e n , t h a t t h e r e e x i s t s a s l e e p - i n d u c i n g e f f e c t of abnormal motion and t h a t t h i s e f f e c t , a l t h o u g h c a p a b l e of b e i n g i n d u c e d by the same s t i m u l i t h a t can provoke motion s i c k n e s s , i s a s e p a r a t e and d i s t i n c t phenomenon. A l t h o u g h G r a y b i e l (1969) has s u g g ested t h a t v e s t i b u l a r a c t i v i t y a f f e c t s the n e u r a l mechanisms f o r s l e e p t h r o u g h the a s c e n d i n g r e t i c u l a r f o r m a t i o n , the e x a c t n a t u r e of t h i s s l e e p - i n d u c i n g e f f e c t and i t s p h y s i o l o g i c a l mechanisms remain o b s c u r e . C a lming or T r a n q u i l i z i n g E f f e c t s of Abnormal M o t i o n A number of a u t h o r s have s u g g e s t e d t h a t abnormal v e s t i b u l a r s t i m u l a t i o n i s c a p a b l e of h a v i n g a t r a n q u i l i z i n g or c a l m i n g ef f e c t . 14 I t s h o u l d be noted here t h a t t h e r e a r e d i f f i c u l t i e s i n a t t e m p t i n g t o c h a r a c t e r i z e a p a r t i c u l a r b e h a v i o u r a l e f f e c t as a s o p o r i f i c , c a l m i n g , or t r a n q u i l i z i n g e f f e c t because the b e h a v i o u r a l m a n i f e s t a t i o n s of each of these e f f e c t s may be q u i t e s i m i l a r ( e . g . , reduced locomotor a c t i v i t y , reduced v o c a l i z a t i o n ) . In no case has an attempt been made t o d i s t i n g u i s h among these p o s s i b l e e f f e c t s , and hence i t i s not c l e a r i f t h e s e v a r i o u s d e s c r i p t i o n s of s l e e p - i n d u c i n g or c a l m i n g e f f e c t s r e p r e s e n t the same phenomenon or d i f f e r e n t phenomena. N e v e r t h e l e s s , an apparent c a l m i n g e f f e c t r e s u l t i n g from v e s t i b u l a r s t i m u l a t i o n has been noted i n a v a r i e t y of e x p e r i m e n t a l s i t u a t i o n s (Weeks, 1979). Korner and Thoman (1973), f o r example, compared the r e l a t i v e e f f i c a c y of v e s t i b u l a r s t i m u l a t i o n ( r o c k i n g ) and o t h e r t e c h n i q u e s of c a l m i n g or s o o t h i n g human i n f a n t s . T echniques t h a t i n v o l v e d s h o r t p e r i o d s of v e s t i b u l a r s t i m u l a t i o n were found t o be more e f f e c t i v e than the o t h e r t e c h n i q u e s i n r e d u c i n g the d u r a t i o n of c r y i n g and o t h e r s i g n s of d i s t r e s s . Pederson and Ter V r u g t (1973) and Ter V r u g t and Pederson (1973) found v e r t i c a l r o c k i n g t o be more e f f e c t i v e than o t h e r forms of v e s t i b u l a r s t i m u l a t i o n i n c a l m i n g i n f a n t s and t h i s c a l m i n g e f f e c t was g r e a t e r a t h i g h e r r o c k i n g f r e q u e n c i e s (up t o 72 c y c l e s per m i n u t e ) . At the h i g h e r f r e q u e n c i e s , the c a l m i n g e f f e c t appeared t o g r e a t l y o u t l a s t the d u r a t i o n of the v e s t i b u l a r s t i m u l a t i o n . Recent e v i d e n c e has a l s o s u g gested t h a t b r i e f p e r i o d s of abnormal motion may have some l o n g - t e r m t h e r a p e u t i c v a l u e i n h y p e r - k i n e t i c c h i l d r e n ( B h a t a r a , C l a r k , & A r n o l d , 1978) and i n non - p a r a n o i d s c h i z o p h r e n i c s ( B a i l e y , 1978). Exposure of m e n t a l l y i l l 15 p a t i e n t s t o abnormal motion environments as a form of t h e r a p y (or management) has a s u r p r i s i n g l y l o n g h i s t o r y ( L i n d z e y , H a l l , & Thompson, 1975, p. 670). However, the e f f e c t i v e n e s s of t h i s t r e a t m e n t i s y e t t o be d e t e r m i n e d . In a n i m a l s , v e s t i b u l a r s t i m u l a t i o n has been r e p o r t e d t o reduce d i s t r e s s i n i n f a n t r a t s s e p a r a t e d from t h e i r mothers (Thoman & K o r n e r , 1971) a l t h o u g h the v a l i d i t y of t h i s f i n d i n g has been q u e s t i o n e d by o t h e r s (LaBarba & S t e w a r t , 1978). S t a u b l i and Huston (1979), i n a r e p o r t c o n c e r n i n g a new a v o i d a n c e l e a r n i n g paradigm, s t a t e t h a t r a t s were swung back and f o r t h a t the end of the e x p e r i m e n t e r ' s o u t s t r e t c h e d arm i n o r d e r t o "calm"them b e f o r e placement i n the e x p e r i m e n t a l a p p a r a t u s . The term "calmed" i s not f u r t h e r d e f i n e d but p o s s i b l y means t h a t the a n i m a l remained m o t i o n l e s s when p l a c e d i n the a p p a r a t u s . T h i s d e c r e a s e i n motor a c t i v i t y i n r a t s has a l s o been noted i n response t o exposure t o a r o t a t i n g open f i e l d ( E s k i n & R i c c i o , 1966). A l t h o u g h i t i s not y e t c l e a r whether the term " c a l m i n g " i s an adequate l a b e l f o r such e f f e c t s , the e v i d e n c e i s q u i t e c l e a r t h a t abnormal v e s t i b u l a r a c t i v i t y can reduce an organism's r e a c t i v i t y t o i t s environment. A n t i n o c i c e p t i v e E f f e c t s of Abnormal Mot i o n A b r i e f p e r i o d of s w i n g i n g motion or v e r t i c a l o s c i l l a t i o n , such as t h a t u t i l i z e d by S t a u b l i & Huston (1979), produces an e f f e c t commonly observed i n the a n i m a l l a b o r a t o r y . A n i m a l s u n d e r g o i n g t h i s t r e a t m e n t appear calmed and r e a c t much l e s s v i o l e n t l y t o an i n j e c t i o n or o t h e r a c u t e n o x i o u s t r e a t m e n t than do a n i m a l s not s u b j e c t e d t o abnormal m o t i o n . 16 T h i s s e e m i n g l y reduced r e a c t i v i t y t o n o x i o u s s t i m u l i f o l l o w i n g a b r i e f p e r i o d of abnormal motion has l e d t o the f o r t u i t o u s f i n d i n g of a p o s s i b l e endogenous p a i n m o d u l a t i o n system t h a t i s t r i g g e r e d by v e s t i b u l a r s t i m u l a t i o n . Gray ( u n p u b l i s h e d d a t a , 1979) e n c l o s e d l a b o r a t o r y r a t s i n c y l i n d r i c a l r e s t r a i n i n g tubes and exposed the r a t s t o e i t h e r 25 sec of manually g e n e r a t e d back and f o r t h s w i n g i n g motion (180° o s c i l l a t i o n s i n a 1.5 m di a m e t e r v e r t i c a l a r c , l o n g i t u d i n a l a x i s of r a t p a r a l l e l t o the p l a n e of r o t a t i o n , a p p r o x i m a t e l y 15 c y c l e s per s e s s i o n ) , or an e q u i v a l e n t p e r i o d of comparable r e s t r a i n t o n l y . Immediately a f t e r the motion or r e s t r a i n t , a s t a n d a r d h o t - w a t e r t e s t f o r a n a l g e s i a ( G r o t t o & Sulman, 1967; S e w e l l & Spencer, 1976) was a d m i n i s t e r e d . D u r i n g the t e s t , the t a i l of the r a t was immersed i n hot (55° C) water and the l a t e n c i e s t o the f i r s t movement of the t a i l and l a t e n c y t o complete w i t h d r a w a l of the t a i l from the water were r e c o r d e d . As shown i n F i g u r e 1, r a t s t h a t had been exposed t o abnormal motion had s i g n i f i c a n t l y l o n g e r l a t e n c i e s t o both f i r s t movement and t a i l w i t h d r a w a l (t=2.74, df=10, p<.05; t=4.15, df=10, p<.05, r e s p e c t i v e l y ) . I t would seem from t h e s e d a t a t h a t t h e r e e x i s t s a q u a n t i f i a b l e decrement i n the r e s p o n s i v e n e s s of r a t s t o a n o x i o u s c h a l l e n g e f o l l o w i n g abnormal motion i n space. The e x a c t n a t u r e of t h i s a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s unknown and one of the p r i m a r y purposes of the p r e s e n t t h e s i s was t o f u r t h e r e x p l o r e the n a t u r e of t h i s a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . The a n t i n o c i c e p t i v e reponse was chosen f o r f u r t h e r 17 FIGURE 1. Mean t a i l movement and t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed t o b r i e f p e r i o d s of motion or r e s t r a i n t . L i n e s on bars i n d i c a t e s t a n d a r d e r r o r of the mean. 18 O CD > O L U 9 8 7 6 5 4 3 2 1 Q TAIL MOVEMENT TAIL WITHDRAWAL MOTION RESTRAINT 19 i n t e n s i v e s t u d y f o r a number of r e a s o n s . F i r s t , the stu d y of an a n t i n o c i c e p t i v e response t o abnormal motion may p r o v i d e i n f o r m a t i o n r e l a t i n g t o endogenous p a i n c o n t r o l mechanisms. Endogenous p a i n c o n t r o l mechanisms, i n f e r r e d by c o n t r o l of p a i n by n o n - p h a r m a c o l o g i c a l a n a l g e s i c a g e n t s , have been thought t o e x i s t f o r some time (see M e l z a c k , 1973; Melzack & D e n n i s , 1978). However, l i t t l e i n f o r m a t i o n c o n c e r n i n g the u n d e r l y i n g n e u r o c h e m i c a l m e d i a t i o n was a v a i l a b l e u n t i l the r e c e n t d i s c o v e r y of endogenous o p i a t e p e p t i d e s i n the c e n t r a l nervous system ( f o r r e v i e w s , see Ba r c h a s , A k i l , E l l i o t , Holman, & Watson, 1978; G o l d s t e i n , 1978; K o s t e r l i t z & Hughes, 1978; T e r e n i u s , 1978) These o p i a t e p e p t i d e s a r e presumed t o be r e l e a s e d i n response t o some s t i m u l i and a c t a t s t e r e o s p e c i f i c r e c e p t o r s i t e s (Snyder, 1975; Snyder & P e r t , 1975) i n much the same f a s h i o n as the morphine m o l e c u l e (Snyder, 1977). In a d d i t i o n t o t h i s endogenous o p i a t e model of endogenous p a i n m o d u l a t i o n , i t appears t h a t a n o n - o p i a t e form of endogenous p a i n m o d u l a t i o n may a l s o e x i s t ( e . g . Bodnar, K e l l y , B r u t u s , Greenman, & Glusman, 1980; Bodnar, K e l l y , S t e i n e r , & Glusman, 1978; S p i a g g i a , Bodnar, K e l l y , & Glusman, 1979). I f t h e s e mechanisms and the s t i m u l i t h a t a c t i v a t e them c o u l d be e l u c i d a t e d , the a n t i n o c i c e p t i v e e f f e c t of abnormal v e s t i b u l a r s t i m u l a t i o n c o u l d c o n c e i v a b l y have some a p p l i c a t i o n as a n o n - p h a r m a c o l o g i c a l means of p a i n c o n t r o l . Second, an i n v e s t i g a t i o n of the p h y s i o l o g i c a l mechanisms u n d e r l y i n g the e a s i l y q u a n t i f i a b l e a n t i n o c i c e p t i v e e f f e c t of abnormal v e s t i b u l a r s t i m u l a t i o n may p r o v i d e i n f o r m a t i o n r e l a t i n g t o t he mechanisms u n d e r l y i n g the o t h e r b e h a v i o u r a l e f f e c t s of abnormal m o t i o n . I t i s p o s s i b l e t h a t abnormal v e s t i b u l a r 20 a c t i v i t y a c t i v a t e s a s i n g l e p h y s i o l o g i c a l mechanism t h a t may then be m a n i f e s t i n a v a r i e t y of b e h a v i o u r a l changes. On the o t h e r hand, i t i s a l s o p o s s i b l e t h a t abnormal v e s t i b u l a r s t i m u l a t i o n a c t i v a t e s a number of d i f f e r e n t mechanisms, each r e s p o n s i b l e f o r a p a r t i c u l a r b e h a v i o u r a l e f f e c t . T h i r d , the use of an e a s i l y q u a n t i f i e d , p r e v i o u s l y v a l i d a t e d b e h a v i o u r a l measure a l l o w s a r e l a t i v e l y p r e c i s e e v a l u a t i o n of the a n t i n o c i c e p t i v e e f f e c t s of v a r i o u s t y p e s and d u r a t i o n s of m o t i o n . Hence, the e f f e c t s and e f f e c t i v e n e s s of v a r i o u s t y p e s and d u r a t i o n s of motion may be e a s i l y i n v e s t i g a t e d . The e x p e r i m e n t s d e s c r i b e d i n the p r e s e n t t h e s i s a r e p r e s e n t e d i n the f o l l o w i n g sequence. In S e c t i o n I , the e x i s t e n c e of an a n t i n o c i c e p t i v e response t o abnormal motion was c o n f i r m e d , and p a r a m e t r i c d a t a c o n c e r n i n g the t ype and d u r a t i o n of motion e f f e c t i v e i n i n d u c i n g a n t i n o c i c e p t i o n and the d u r a t i o n and magnitude of the a n t i n o c i c e p t i v e response a r e p r e s e n t e d . The main purpose of the e x p e r i m e n t s i n t h i s s e c t i o n t h e r e f o r e , was t o e x p l o r e the c h a r a c t e r i s t i c s of the a n t i n o c i c e p t i v e e f f e c t and the p r o p e r t i e s of the s t i m u l u s t h a t a r e e f f e c t i v e i n i n d u c i n g the e f f e c t . S e c t i o n I I i n c l u d e s a s e r i e s of e x p e r i m e n t s t h a t were d i r e c t e d a t d e t e r m i n i n g the r o l e of the v e s t i b u l a r system i n the a n t i n o c i c e p t i v e e f f e c t of m o t i o n . I t i s p o s s i b l e t h a t s t i m u l i e f f e c t i v e i n i n d u c i n g a n t i n o c i c e p t i o n have l i t t l e or no e f f e c t on v e s t i b u l a r f u n c t i o n . The f i r s t experiment i n t h i s s e c t i o n i n v e s t i g a t e d t h i s p o s s i b i l i t y by e x amining the e f f e c t s of motion i n a n i m a l s whose v e s t i b u l a r a p p a r a t u s had been r e n d e r e d non-21 f u n c t i o n a l . A d d i t i o n a l e x p e r i m e n t s i n v o l v i n g b o t h l e s i o n a n d e l e c t r i c a l s t i m u l a t i o n t e c h n i q u e s a t t e m p t e d t o i n v e s t i g a t e t h e r . o l e o f c e n t r a l v e s t i b u l a r c o m p o n e n t s i n t h e a n t i n o c i c e p t i v e e f f e c t o f a b n o r m a l m o t i o n . S e c t i o n I I I w a s d e v o t e d t o a n i n v e s t i g a t i o n o f t h e p o s s i b l e p h y s i o l o g i c a l m e c h a n i s m s o f m o t i o n - i n d u c e d a n t i n o c i c e p t i o n a n d u s e d a v a r i e t y o f p h a r m a c o l o g i c a l a n d s u r g i c a l m a n i p u l a t i o n s . O t h e r b e h a v i o u r a l e f f e c t s o f v e s t i b u l a r s t i m u l a t i o n i n a n i m a l s w e r e e x a m i n e d i n S e c t i o n IV. M o t i o n s i c k n e s s a n d i t s p h y s i o l o g i c a l b a s i s w e r e i n v e s t i g a t e d i n t h e f i r s t t w o e x p e r i m e n t s o f t h i s s e c t i o n , a n d a t h i r d e x p e r i m e n t w a s d i r e c t e d a t q u a n t i f y i n g a p o s s i b l e a n x i o l y t i c o r c a l m i n g e f f e c t o f v e s t i b u l a r s t i m u l a t i o n . 22 SECTION I - The A n t i n o c i c e p t i v e E f f e c t s of Abnormal M o t i o n The e x p e r i m e n t s d e s c r i b e d i n S e c t i o n I were d i r e c t e d at c o n f i r m i n g the the e x i s t e n c e of an> a n t i n o c i c e p t i v e e f f e c t of abnormal motion and e x p l o r i n g some of the parameters g o v e r n i n g the e f f e c t . S p e c i f i c a l l y , Experiment 1 c o n f i r m e d the e x i s t e n c e of the a n t i n o c i c e p t i v e e f f e c t and examined the d u r a t i o n of t h i s e f f e c t , whereas Experiment 2 examined the a n t i n o c i c e p t i v e e f f e c t s of v a r i o u s t y p e s of m o t i o n . E x p e r i m e n t s 3 and 4 e x p l o r e d two i m p o r t a n t i s s u e s r e l a t e d t o the phenomenon: the degree of v e s t i b u l a r d y s f u n c t i o n produced by the abnormal motion and the g e n e r a l i t y of the a n t i n o c i c e p t i v e e f f e c t . The f i n a l e xperiment i n t h i s s e c t i o n , Experiment 5, examined the d u r a t i o n of the motion s t i m u l u s n e c e s s a r y t o e l i c i t an a n t i n o c i c e p t i v e e f f e c t and the d u r a t i o n of the a n t i n o c i c e p t i v e response e l i c i t e d by a complex form of m o t i o n . In t h e s e and subsequent s t u d i e s , the r a t h o t - w a t e r t a i l immersion t e s t ( t a i l f l i c k t e s t , t a i l w i t h d r a w a l t e s t ) was u t i l i z e d as an assay f o r the presence of an a n t i n o c i c e p t i v e e f f e c t ( G r o t t o & Sulman, 1967; S e w e l l & Spencer, 1976). T h i s and o t h e r t e s t s u t i l i z i n g exposure of the r a t ' s t a i l t o a t h e r m a l s t i m u l u s ( i . e . , r a d i a n t h e a t , D'Amour & S m i t h , 1941) have been w i d e l y used as measures of a n a l g e s i a ( G l i c k , 1976). The t a i l f l i c k or w i t h d r a w a l response was chosen as the dependent measure f o r a v a r i e t y of r e a s o n s . The t a i l f l i c k response i s mediated s p i n a l l y (Hayes, Bennet, Newlon, & Mayer, 1978), and hence does not r e q u i r e the i n t e g r i t y of s u p r a - s p i n a l s t r u c t u r e s f o r i t s appearance (Hayes, P r i c e , Bennet, W i l c o x , & Mayer, 1978). The t a i l w i t h d r a w a l t e s t a l s o a c c u r a t e l y r e f l e c t s 23 and p r e d i c t s the r e l a t i v e potency of v a r i o u s a n a l g e s i c a gents i n humans ( e . g . , S e w e l l & Spencer, 1976). The t a i l w i t h d r a w a l response has o t h e r advantages i n t h a t i t i s a s t r a i g h t f o r w a r d and e a s i l y s c o r e d b e h a v i o u r a l response and the exposure t o the p a i n - p r o d u c i n g s t i m u l u s i s t e r m i n a t e d by the s u b j e c t , thus e n s u r i n g t h a t e x c e s s i v e p a i n i s not produced. The use of h o t -water as the p a i n - p r o d u c i n g s t i m u l u s has advantages i n t h a t the tem p e r a t u r e of the s t i m u l u s may be e a s i l y c o n t r o l l e d and the t h e r m a l s t i m u l u s a p p l i e d u n i f o r m l y , i n c o n t r a s t t o r a d i a n t heat t e c h n i q u e s t h a t r e q u i r e b l a c k e n i n g of the s k i n t o i n s u r e u n i f o r m s t i m u l u s i n t e n s i t y . Experiment 1 Experiment 1 was an attempt t o r e p l i c a t e and f u r t h e r e x p l o r e the n a t u r e of the a n t i n o c i c e p t i v e e f f e c t found by Gray ( u n p u b l i s h e d d a t a , 1979) u s i n g s w i n g i n g as means of i n d u c i n g a n t i n o c i c e p t i o n . Repeated t a i l w i t h d r a w a l t e s t s were conducted f o l l o w i n g c e s s a t i o n of the motion s t i m u l u s i n o r d e r t o det e r m i n e th e d u r a t i o n of the e f f e c t . In a d d i t i o n , the e f f e c t i v e n e s s of two d i f f e r e n t motion d u r a t i o n s i n p r o d u c i n g a n t i n o c i c e p t i o n was e v a l u a t e d . METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 30 n a i v e male hooded (Long-Evans) r a t s ( o b t a i n e d from Canadian B r e e d i n g Farms and L a b o r a t o r i e s , S t . C o n s t a n t , Que.) w e i g h i n g a p p r o x i m a t e l y 350 gm. The r a t s were housed i n groups of s i x i n s t a n d a r d hanging w i r e cages (24 X 64 X 18 cm) under a r e v e r s e d 24 12 hr l i g h t / d a r k ( l i g h t s o f f a t 0800) l i g h t i n g c y c l e . A l l s u b j e c t s remained i n the c o l o n y room f o r a minimum of 14 days p r i o r t o p a r t i c i p a t i o n i n the e x p e r i m e n t . Food and water were f r e e l y a v a i l a b l e and the c o l o n y t e m p e r a t u r e was n o m i n a l l y m a i n t a i n e d a t 21° C. App a r a t u s A c a r d b o a r d tube, 21.5 cm l o n g and 7.5 cm i n d i a m e t e r s e r v e d as the r e s t r a i n i n g d e v i c e . Two removable v e n t i l a t e d p l a s t i c caps a t each end of the tube p r e v e n t e d the r a t s from e s c a p i n g . The dimensions of the r e s t r a i n i n g tube were such t h a t the r a t s were not unduly c o n s t r a i n e d y e t c o u l d not e a s i l y r e v e r s e d i r e c t i o n w i t h i n the t u b e . A c o n s t a n t temperature c i r c u l a t i n g water bath ( B l u e M, M a g n i - W h i r l c o n s t a n t temperature bath) was used t o p r o v i d e a c o n s t a n t (52° C) t h e r m a l s t i m u l u s . P r o c e d u r e R a t s were randomly a s s i g n e d t o one of t h r e e c o n d i t i o n s (n = 1 0 ) ; a r e s t r a i n t - o n l y c o n t r o l group, or t o one of two d i f f e r e n t motion d u r a t i o n c o n d i t i o n s . The motion was a m a n u a l l y - p r o d u c e d s e m i c i r c u l a r o s c i l l a t i o n of the r e s t r a i n i n g tube produced w i t h the l o n g i t u d i n a l a x i s of the r a t a l i g n e d p a r a l l e l t o the p l a n e of r o t a t i o n . O s c i l l a t i o n was t h r o u g h a v e r t i c a l 180 a r c a t an approximate r a t e of 50 t r a v e r s e s of the a r c ( i . e . swings, back and f o r t h ) per min. The 10 r a t s i n one e x p e r i m e n t a l group were exposed t o 30 swings, whereas the r a t s i n the o t h e r e x p e r i m e n t a l group were exposed t o 200 swing s . Rats i n the r e s t r a i n t c o n d i t i o n were p l a c e d i n the r e s t r a i n i n g tubes f o r a p e r i o d of time e q u i v a l e n t t o t h a t r e q u i r e d t o complete 200 swings i n the motion c o n d i t i o n ( a p p r o x i m a t e l y 4 m i n ) . A l l r a t s were t e s t e d i n 25 squads of t h r e e r a t s each w i t h one r a t from each of the t h r e e c o n d i t i o n s i n each squad. Immediately f o l l o w i n g the t e r m i n a t i o n of the a p p r o p r i a t e motion or r e s t r a i n t t r e a t m e n t , the r e a r cap of the r e s t r a i n i n g tube was removed and the r a t ' s t a i l was a l l o w e d t o hang f r e e from the tu b e . The t a i l was then lowered t o a depth of 8 cm i n t o the hot (52° C) water. At the time of immersion i n t o the hot water, an e l e c t r o n i c s topwatch was s t a r t e d . The stopwatch was stopped when the r a t had c o m p l e t e l y removed i t s t a i l from the hot water and the l a t e n c y t o do so was then r e c o r d e d . The r a t and r e s t r a i n i n g tube were then p l a c e d i n t o a w i r e mesh h o l d i n g cage t h a t had d i m e n s i o n s such t h a t r e p l a c i n g the r e a r cap was not n e c e s s a r y t o p r e v e n t escape from the tube. Another a n a l g e s i a t e s t was conducted 180 sec f o l l o w i n g the t e r m i n a t i o n of the motion or r e s t r a i n t t r e a t m e n t . A f i n a l a n a l g e s i a t e s t was conducted 300 sec f o l l o w i n g the t e r m i n a t i o n of the t r e a t m e n t . The e x p e r i m e n t a l d e s i g n was thus a 3 X 3 r e p e a t e d measures w i t h the t h r e e t r e a t m e n t c o n d i t i o n s and the 3 t r e a t m e n t - t e s t i n t e r v a l s . A l l t e s t i n g was conducted i n the l a t e a f t e r n o o n ( a p p r o x i m a t e l y 1600 hr ) under normal room i l l u m i n a t i o n and t e m p e r a t u r e . L a t e n c y t o f i r s t movement of the t a i l was not r e c o r d e d i n the p r e s e n t s t u d y or i n subsequent s t u d i e s a l t h o u g h i t had been r e c o r d e d i n the Gray ( u n p u b l i s h e d d a t a , 1979) study d e s c r i b e d e a r l i e r . In the p r e v i o u s s t u d y , t a i l movement l a t e n c y was found t o c o r r e l a t e h i g h l y (rho= +.729, p<.05, Spearman rank o r d e r c o r r e l a t i o n ) w i t h t a i l w i t h d r a w a l l a t e n c y , and because t a i l w i t h d r a w a l was f e l t t o be a l e s s ambiguous b e h a v i o u r a l 26 measure, the movement-latency measure was e x c l u d e d from subsequent i n v e s t i g a t i o n s . RESULTS AND DISCUSSION As shown i n F i g u r e 2, exposure of r a t s to e i t h e r the 30- or 200- swing c o n d i t i o n r e s u l t e d i n a s i g n i f i c a n t (F=7.57, df=2/27, p<.05) i n c r e a s e i n t a i l w i t h d r a w a l l a t e n c i e s . P o s t hoc t e s t s (Tukey) i n d i c a t e d no s i g n i f i c a n t d i f f e r e n c e s between the e f f e c t s of 30 or 200 swings (p>.05). A l t h o u g h the e f f e c t of r e p e a t e d t e s t s was not s i g n i f i c a n t (F=2.35, df=2/54, p>.05), a s i g n i f i c a n t i n t e r a c t i o n between t r e a t m e n t and r e p e a t e d t e s t s (F=3.02, df=27/54, p<.05) suggested t h a t the a n t i n o c i c e p t i v e e f f e c t of motion d e c l i n e d w i t h t i m e . Post hoc a n a l y s i s i n d i c a t e d a s i g n i f i c a n t e f f e c t of motion a t the 0- sec and 180-sec t e s t t i m e s (p<.05) but no s i g n i f i c a n t d i f f e r e n c e s were found between r e s t r a i n t and the two motion c o n d i t i o n s a t 300 s e c . These r e s u l t s c o n f i r m the e x i s t e n c e of the a n t i n o c i c e p t i v e e f f e c t of exposure t o s w i n g i n g motion t h a t had been p r e v i o u s l y n o t e d i n our l a b o r a t o r y (Gray, u n p u b l i s h e d d a t a ) . A s t i m u l u s c o n s i s t i n g of 200 swings was no more e f f e c t i v e than one of 30 swings i n p r o d u c i n g the i n c r e a s e i n t a i l w i t h d r a w a l l a t e n c i e s . The e f f e c t a l s o appears t o decay i n a r e l a t i v e l y s h o r t p e r i o d of t i m e , a s t a i l w i t h d r a w a l l a t e n c i e s d i d not d i f f e r among groups i n the 300 sec t e s t . T h i s would suggest t h a t whatever p h y s i o l o g i c a l mechanism u n d e r l i e s t h i s e f f e c t , i t i s a c t i v a t e d t o some maximum i n a s h o r t p e r i o d of time and d e c l i n e s r a p i d l y f o l l o w i n g removal of the p r o v o c a t i v e s t i m u l u s . I t appears t h e n , t h a t t h e r e i s a l a r g e r e l i a b l e decrement i n the r a t s r e a c t i o n t o a n o x i o u s s t i m u l u s f o l l o w i n g exposure t o 27 FIGURE 2. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed r e s t r a i n t or one of two d i f f e r e n t motion c o n d i t i o n s Experiment 1. V e r t i c a l l i n e s i n d i c a t e s t a n d a r d e r r o r s . 28 • T I 0 180 300 Time of Test (sec) 29 at l e a s t one form of abnormal m o t i o n . I t i s not c l e a r however, e x a c t l y what a t t r i b u t e s of the motion were i m p o r t a n t i n e l i c i t i n g t h i s a n t i n o c i c e p t i v e r e s p o n s e . Experiment 2 I t i s d i f f i c u l t t o i d e n t i f y e x a c t l y which f e a t u r e s a r e i m p o r t a n t i n e l i c i t i n g the a n t i n o c i c e p t i v e reponse t o abnormal motion when s w i n g i n g i s used as the s t i m u l u s . Not o n l y i s the s w i n g i n g motion d i f f i c u l t t o c o n t r o l i n terms of degree and d u r a t i o n , i t a l s o confounds v e r t i c a l and h o r i z o n t a l l i n e a r a c c e l e r a t i o n w i t h a n g u l a r a c c e l e r a t i o n components. These t y p e s of motion a r e thought t o be d e t e c t e d ( i n mammals, a t l e a s t ) by two r e l a t i v e l y independent components of the p e r i p h e r a l v e s t i b u l a r a p p a r a t u s ( G o l d s t e i n , 1974; Johnson & Jongkees, 1974; Reason & Brand, 1975). One component, the l a b y r i n t h i n e c a n a l s , are p r i m a r i l y r e s p o n s i b l e f o r d e t e c t i n g a n g u l a r a c c e l e r a t i o n s i n t h r e e a p p r o x i m a t e l y o r t h o g o n a l p l a n e s . W i t h i n each of t h r e e narrow f l u i d - f i l l e d s e m i - c i r c u l a r c a n a l s l i e s a ' p l u g ' of g e l a t i n o u s m a t e r i a l , the c u p u l a . A n g u l a r a c c e l e r a t i o n s i n the a p p r o p r i a t e p l a n e cause motion of the f l u i d r e l a t i v e t o the w a l l s of the c a n a l s , and t h i s r e l a t i v e movement of the f l u i d c a u s e s a d i s p l a c e m e n t of the c u p u l a p r o p o r t i o n a l t o the degree of a c c e l e r a t i o n . D i s p l a c e m e n t of the c u p u l a causes d e f o r m a t i o n of the h a i r s of r e c e p t o r c e l l s t h a t a r e embedded i n the base of the c u p u l a . T h i s d e f o r m a t i o n of the h a i r s causes e i t h e r i n h i b i t i o n or e x c i t a t i o n of f i r i n g a c t i v i t y i n the r e c e p t o r c e l l s p r o p o r t i o n a t e t o the amount of h a i r c e l l d e f o r m a t i o n . The second component of the p e r i p h e r a l v e s t i b u l a r organs i s 30 the o t o l i t h i c mechanism, thought t o be p r i m a r i l y s e n s i t i v e t o l i n e a r and g r a v i t a t i o n a l a c c e l e r a t i o n . A dense f i b r o u s m a t r i x c o n t a i n i n g c a l c i u m c r y s t a l s o v e r l i e s the r e c e p t o r c e l l a r e a s (th e maculae) of both the u t r i c l e and s a c c u l e . These r e c e p t o r a r e a s a re s i t u a t e d so t h a t the s a c c u l a r o t o l i t h i s p r i m a r i l y v e r t i c a l i n o r i e n t a t i o n and the u t r i c u l a r o t o l i t h i s h o r i z o n t a l . A c c e l e r a t i o n s i n a p l a n e p a r a l l e l t o the o r i e n t a t i o n of an o t o l i t h causes d e f o r m a t i o n of h a i r c e l l s embedded i n the o v e r l y i n g m a t r i x . T h i s h a i r c e l l d e f o r m a t i o n causes e x c i t a t i o n or i n h i b i t i o n of r e c e p t o r c e l l a c t i v i t y i n a manner s i m i l a r t o t h a t d e s c i b e d above. Given t h a t the s w i n g i n g motion i s composed of both l i n e a r and a n g u l a r a c c e l e r a t i o n components, i t i s p o s s i b l e t h a t one of th e s e components may be more i m p o r t a n t than the o t h e r i n e l i c i t i n g the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . D i f f e r e n t t y p e s of motion do appear t o be d i f f e r e n t i a l l y e f f e c t i v e i n e l i c i t i n g v a r i o u s b e h a v i o u r a l e f f e c t s . For example, v e r t i c a l o s c i l l a t i o n was found t o be much more e f f e c t i v e than h o r i z o n t a l o s c i l l a t i o n i n s o o t h i n g i n f a n t s (Pederson & Ter V r u g t , 1973; Ter V r u g t & Pederson, 1973), and complex c o r i o l i s - t y p e motion i s much more e f f e c t i v e than s i m p l e r o t a t i o n i n i n d u c i n g motion s i c k n e s s (Reason & Brand, 1975). A c c o r d i n g l y , Experiment 2 was d e s i g n e d t o i n v e s t i g a t e the a n t i n o c i c e p t i v e e f f e c t s of t h r e e d i f f e r e n t t y p e s of m o t i o n , r o t a t i o n i n a h o r i z o n t a l p l a n e , v e r t i c a l a c c e l e r a t i o n , or a c o m b i n a t i o n of b o t h . Because t h e r e have been r e p o r t s of c i r c a d i a n v a r i a t i o n s i n p a i n p e r c e p t i o n i n r a t s ( F r e d e r i c k s o n , Weshe, & R i c h t e r , 1978; 31 R o s e n f e l d & R i c e , 1979), time of t e s t i n g was i n c l u d e d as an a d d i t i o n a l f a c t o r i n the p r e s e n t e x p e r i m e n t . Time of t e s t i n g was i n v e s t i g a t e d p r i m a r i l y t o d e t e r m i n e a s u i t a b l e time of day ( i . e . , AM v e r s u s PM) f o r subsequent e x p e r i m e n t a t i o n . Experiment 2 was not i n t e n d e d t o be a s y s t e m a t i c e x p l o r a t i o n of c i r c a d i a n v a r i a t i o n . METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 48 n a i v e male hooded r a t s w e i g h i n g a p p r o x i m a t e l y 350 gm. The s u b j e c t s were p u r c h a s e d , housed, and m a i n t a i n e d as i n Experiment 1. Apparatus The a p p a r a t u s used t o a d m i n i s t e r the abnormal motion t r e a t m e n t s i n the p r e s e n t experiment was a h o r i z o n t a l t u r n t a b l e mounted i n a s p r i n g - s u s p e n d e d frame t h a t was f r e e t o move on v e r t i c a l g u i d e r a i l s . A schematic r e p r e s e n t a t i o n of the d e v i c e i s shown i n F i g u r e 3. The r o t a t i o n a l speed of the e l e c t r i c t u r n t a b l e motor c o u l d be a d j u s t e d w i t h a t r a n s f o r m e r and the v e r t i c a l o s c i l l a t i o n r a t e and a m p l i t u d e were c o n t r o l l e d m a n u a l l y . A w i r e mesh cage, mounted on the t u r n t a b l e , p r o v i d e d a c a r r i e r d e v i c e f o r t h e r e s t r a i n i n g tubes d e s c r i b e d i n Experiment 1. The w i r e mesh cage a l l o w e d two r e s t r a i n i n g tubes t o be mounted s i d e - b y - s i d e on the t u r n t a b l e and an a d d i t i o n a l f o u r r e s t r a i n i n g tubes c o u l d be s t a c k e d i n the mesh cage i f n e c e s s a r y . The s l i g h t l y o f f - c e n t r e placement of the tubes r e s u l t e d i n each r a t ' s head b e i n g p l a c e d a p p r o x i m a t e l y 11 cm away from the c e n t r e of r o t a t i o n . In h o r i z o n t a l r o t a t i o n a t 30 RPM, t h i s placement would r e s u l t i n a f o r c e of a p p r o x i m a t e l y 32 FIGURE 3. Schematic r e p r e s e n t a t i o n of the motion d e v i c e used i n Experiment 2: (A) s p r i n g s u s p e n s i o n , (B) v e r t i c a l o s c i l l a t i o n c a b l e , (C) frame, (D) w i r e mesh cage, (E) h o r i z o n t a l t u r n t a b l e , (F) v a r i a b l e speed e l e c t r i c motor, (G) v e r t i c a l g u i d e r a i l s . 33 34 0.14 G e x e r t e d a t the r a t ' s head. T h i s d e v i c e i s s i m i l a r t o t h a t d e s c r i b e d by B r i z z e e and c o-workers ( B r i z z e e , Ordy, & M e h l e r , 19.80; Ordy & B r i z z e e , 1980; Roy & B r i z z e e , 1979) and the motion parameters used i n the p r e s e n t experiment were chosen t o c o i n c i d e w i t h those used by B r i z z e e e t a l . , w i t h i n the l i m i t a t i o n s of the p r e s e n t a p p a r a t u s . The h o r i z o n t a l r o t a t i o n speed was 30 RPM and the v e r t i c a l o s c i l l a t i o n r a t e was a p p r o x i m a t e l y 50 c y c l e s per min w i t h an a m p l i t u d e of a p p r o x i m a t e l y 25 cm. The a n a l g e s i a t e s t i n g a p p a r a t u s was i d e n t i c a l t o t h a t d e s c r i b e d i n Experiment 1. P r o c e d u r e On each of 2 days p r i o r t o the i n i t i a t i o n of t e s t i n g , a l l a n i m a l s were a c c l i m a t e d t o the r e s t r a i n i n g tubes f o r a 5 min p e r i o d a t a p p r o x i m a t e l y 1200 h r . On the day of t e s t i n g , 12 a n i m a l s were randomly a s s i g n e d t o each of f o u r motion c o n d i t i o n s : 1) r e s t r a i n t o n l y , 2) h o r i z o n t a l r o t a t i o n (30 RPM), 3) v e r t i c a l o s c i l l a t i o n (50 c y c l e s per m i n ) , or 4) h o r i z o n t a l r o t a t i o n combined w i t h v e r t i c a l o s c i l l a t i o n . S i x r a t s from each group were t e s t e d b e g i n n i n g a t 0900 hr and the r e m a i n i n g s i x were t e s t e d i n the a f t e r n o o n b e g i n n i n g a t 1400 h r . The e x p e r i m e n t a l d e s i g n was t h u s a 2 X 4 f a c t o r i a l . A l l r a t s were t e s t e d s e q u e n t i a l l y i n squads of f o u r a n i m a l s e a c h , composed of one r a t from each of the f o u r t r e a t m e n t c o n d i t i o n s . Immediately f o l l o w i n g 5 min of exposure t o e i t h e r r e s t r a i n t or t o one of the t h r e e motion c o n d i t i o n s , a h o t - w a t e r t a i l w i t h d r a w a l t e s t was a d m i n i s t e r e d as d e s c r i b e d p r e v i o u s l y . RESULTS AND DISCUSSION The r e s u l t s of Experiment 2 a r e d e p i c t e d i n F i g u r e 4. 35 FIGURE 4. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s i n Experiment 2. R a t s were t e s t e d i n one of f o u r motion c o n d i t i o n s : r e s t r a i n t (REST), h o r i z o n t a l r o t a t i o n (ROT), v e r t i c a l o s c i l l a t i o n (VERT), or v e r t i c a l o s c i l l a t i o n i n c o m b i n a t i o n w i t h h o r i z o n t a l r o t a t i o n (VERT + ROT). 36 Tail Withdrawal Latency (sec) O ^ M W ^ O l d l N l O D c o o • • • • • • • • • • • 33 rn CO —\ H Cr, S J3 ~ i ° o CJ H H a 3 < 1 J3 H r H 1 1 H 37 A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t o v e r a l l i n c r e a s e i n t a i l w i t h d r a w a l l a t e n c i e s f o l l o w i n g exposure t o abnormal motion (F=3.51, df=3/39, p<.05). Post hoc a n a l y s i s (Tukey) i n d i c a t e d t h a t o n l y h o r i z o n t a l r o t a t i o n i n c o m b i n a t i o n w i t h v e r t i c a l o s c i l l a t i o n was e f f e c t i v e i n s i g n i f i c a n t l y e l e v a t i n g t a i l w i t h d r a w a l l a t e n c i e s (p<.05) and no s i g n i f i c a n t d i f f e r e n c e s were found when r e s t r a i n t , h o r i z o n t a l r o t a t i o n , and v e r t i c a l o s c i l l a t i o n were compared (p>.05). As shown i n F i g u r e 4, h o r i z o n t a l r o t a t i o n or v e r t i c a l o s c i l l a t i o n a l o n e produced no s i g n i f i c a n t change. No s i g n i f i c a n t main e f f e c t of time of day was found (F=.28,df=1/39, p>.05) nor was the i n t e r a c t i o n term of the a n a l y s i s s i g n i f i c a n t (F=.19,- df=3/39, p>.05). There d i d however, seem t o be a t r e n d towards g r e a t e r u n i f o r m i t y i n t a i l w i t h d r a w a l s c o r e s i n the a f t e r n o o n t e s t s e s s i o n . Thus most t e s t i n g i n subsequent e x p e r i m e n t s was conducted i n the a f t e r n o o n i n an e f f o r t t o reduce v a r i a n c e . I t would seem from these r e s u l t s t h a t an a n t i n o c i c e p t i v e e f f e c t may be e l i c i t e d by t y p e s of motion o t h e r than the s w i n g i n g motion used i n Experiment 1. The p r e s e n t r e s u l t s f u r t h e r suggest t h a t the a n t i n o c i c e p t i v e e f f e c t i s b e s t e l i c i t e d by r e l a t i v e l y complex forms of motion such as the s w i n g i n g motion used p r e v i o u s l y and the h o r i z o n t a l r o t a t i o n i n c o m b i n a t i o n w i t h v e r t i c a l o s c i l l a t i o n u t i l i z e d i n the p r e s e n t s t u d y . R e l a t i v e l y s i m p l e forms of motion such as h o r i z o n t a l r o t a t i o n or v e r t i c a l o s c i l l a t i o n do not apppear t o e l i c i t any a p p r e c i a b l e degree of a n t i n o c i c e p t i o n , a t l e a s t not a t the s t i m u l u s i n t e n s i t i e s and d u r a t i o n s used h e r e . I t would seem t h e n , t h a t d i f f e r e n t t y p e s of motion a r e d i f f e r e n t i a l l y 38 e f f e c t i v e i n p r o d u c i n g an a n t i n o c i c e p t i v e e f f e c t . C o n c l u s i o n s r e g a r d i n g a n g u l a r and l i n e a r a c c e l e r a t i o n components must be advanced c a u t i o u s l y however, due t o the l i m i t e d range of motions used and the somewhat i m p r e c i s e c o n t r o l of the i n t e n s i t y of a c c e l e r a t i o n i n the p r e s e n t e x p e r i m e n t . A l t h o u g h no f o r m a l comparison can be made, i t s h o u l d be noted t h a t the degree of a n a l g e s i a (measured by t a i l w i t h d r a w a l l a t e n c y ) produced by the complex motion t r e a t m e n t i n the p r e s e n t experiment ( a p p r o x i m a t e l y 35% over c o n t r o l v a l u e s ) was not as g r e a t as the degree of a n a l g e s i a produced by the much s h o r t e r d u r a t i o n s w i n g i n g motion used i n Experiment 1 ( a p p r o x i m a t e l y 86% over c o n t r o l v a l u e s ) . One p o s s i b l e c r i t i c i s m c o n c e r n i n g the use of abnormal motion t o e l i c i t a n t i n o c i c e p t i o n may be t h a t the apparent a n t i n o c i c e p t i o n produced by abnormal motion may r e f l e c t n o t h i n g more than an a r t i f a c t of v e s t i b u l a r s t i m u l a t i o n . That i s , i t i s p o s s i b l e t h a t ' d i z z i n e s s ' or ' v e r t i g o ' produced by abnormal v e s t i b u l a r s t i m u l a t i o n (Reason & Brand, 1975) i n t e r f e r e s i n some f a s h i o n w i t h the r a t s a b i l i t y t o withdraw i t s t a i l from the n o x i o u s s t i m u l u s . Experiment 3 was d e s i g n e d t o t e s t t h i s h y p o t h e s i s . Experiment 3 I f d i z z i n e s s or v e r t i g o i s r e p o n s i b l e i n some manner f o r i n h i b i t i n g t he r a t s a b i l i t y t o withdraw i t s t a i l from the h o t -water used i n the a n a l g e s i a t e s t , e i t h e r t h r o u g h some form of motor d i s r u p t i o n or a d i s t r a c t i o n e f f e c t , one would expect the e f f i c a c y of a p a r t i c u l a r motion t r e a t m e n t i n i n d u c i n g a n a l g e s i a 39 t o be c o r r e l a t e d w i t h the degree of d i z z i n e s s or v e r t i g o produced by t h a t motion t r e a t m e n t . The purpose of Experiment 3 was t o compare the f o u r motion t r e a t m e n t s used i n Experiment 2 i n terms of the degree of g e n e r a l v e s t i b u l a r d y s f u n c t i o n i n d u c e d by each. METHOD The day f o l l o w i n g the c o m p l e t i o n of Experiment 2, s i x r a t s were s e l e c t e d a t random from each of the f o u r motion groups used i n Experiment 2 and s u b j e c t e d t o the same motion t r e a t m e n t they had p r e v i o u s l y r e c e i v e d . Immediately f o l l o w i n g the t e r m i n a t i o n of the 5 min t r e a t m e n t p e r i o d , each r a t underwent a b a l a n c e beam t e s t . The b a l a n c e beam t e s t was a s l i g h t l y m o d i f i e d v e r s i o n of the t e s t f o r v e s t i b u l a r d y s f u n c t i o n d e s c r i b e d by Modianos and P f a f f (1976). The r a t was p l a c e d l e n g t h w i s e i n the c e n t r e of a 2 cm X 61 cm suspended beam. D u r i n g a 10-sec t e s t , the b e h a v i o u r of the r a t was s c o r e d as f o l l o w s : 4 - i f the r a t walked s t e a d i l y t o one end of the beam, 3 - i f the r a t moved t o one end of the beam but appeared unsteady, 2 - i f the r a t d i d not move a l o n g the beam but appeared s t a b l e , 1 - i f the r a t d i d not move a l o n g the beam and appeared u n s t a b l e , and 0 - i f the r a t f e l l from the beam. Sc o r e s a t t a i n e d by normal r a t s i n our l a b o r a t o r y g e n e r a l l y range from 2 t o 4. RESULTS AND DISCUSSION As i l l u s t r a t e d i n F i g u r e 5, b a l a n c e s c o r e s were s i g n i f i c a n t l y d e c r e a s e d by p r e t e s t exposure t o abnormal motion (F=7.48, df=3/20, p<.05). A l t h o u g h F i g u r e 5 s u g g e s t s t h a t t h i s e f f e c t was g r e a t e s t i n the combined h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n c o n d i t i o n , the t h r e e motion t r e a t m e n t s d i d 40 FIGURE 5. Mean b a l a n c e beam s c o r e s f o r r a t s t e s t e d i n one of f o u r motion c o n d i t i o n s i n Experiment 3: r e s t r a i n t (REST), h o r i z o n t a l r o t a t i o n (ROT), v e r t i c a l o s c i l l a t i o n (VERT), or / v e r t i c a l o s c i l l a t i o n combined w i t h h o r i z o n t a l r o t a t i o n (VERT & ROT). 42 not d i f f e r s i g n i f i c a n t l y (p>.05). B a l a n c e s c o r e s i n the v e r t i c a l o s c i l l a t i o n and combined c o n d i t i o n were, however, s i g n i f i c a n t l y l e s s than t h o s e i n the r e s t r a i n t c o n d i t i o n (p<.05). I t would seem from the r e s u l t s of Experiment 3 t h a t exposure t o abnormal motion does induce d i z z i n e s s or some type of v e s t i b u l a r d y s f u n c t i o n i n the r a t , a t l e a s t as i n f e r r e d by the r a t s a b i l i t y t o m a i n t a i n i t s b a l a n c e on a narrow beam. The degree of d e f i c i t i n b a l a n c i n g a b i l i t y produced by the v a r i o u s motion t r e a t m e n t s a l s o appears t o r o u g h l y c o r r e s p o n d w i t h the a b i l i t y of t h e s e t r e a t m e n t s t o induce a n a l g e s i a (compare F i g u r e s 4 and 5 ) . The h o r i z o n t a l r o t a t i o n combined w i t h v e r t i c a l o s c i l l a t i o n produced the g r e a t e s t degree of a n a l g e s i a i n Experiment 2 and produced the g r e a t e s t degree of d i s r u p t i o n i n the b a l a n c i n g t a s k i n the p r e s e n t e x p e r i m e n t . A l t h o u g h t h e r e does appear t o be a r e l a t i o n s h i p between the a b i l i t y of an abnormal motion t r e a t m e n t t o induce a n a l g e s i a and i t s a b i l i t y t o produce v e s t i b u l a r d y s f u n c t i o n , i t i s not c l e a r i f t h i s r e l a t i o n s h i p i s c a u s a l i n n a t u r e . I f d i z z i n e s s and a n a l g e s i a a r e both e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n , one might expect t h a t t r e a t m e n t s e f f e c t i v e i n p r o d u c i n g one e f f e c t would a l s o be e f f e c t i v e i n e l i c i t i n g t he o t h e r . For example, a l t h o u g h d i z z i n e s s , nausea, v o m i t i n g , and d r o w s i n e s s a r e a l l e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n , t h e r e may be no c a u s a l r e l a t i o n s h i p between them. On the b a s i s of the r e s u l t s of t h e p r e s e n t experiment however, i t i s d i f f i c u l t t o r e s o l v e the problem and t h i s i s s u e i s t r e a t e d a t l e n g t h e l s e w h e r e i n t h i s t h e s i s (see S e c t i o n I I , E x p e r i m e n t s 7 and 8 ) . 43 Experiment 4 I f abnormal motion does produce an a n t i n o c i c e p t i v e e f f e c t , then t h i s e f f e c t s h o u l d a l s o be apparent when the r a t s r e a c t i o n t o a n o x i o u s s t i m u l u s i s measured u s i n g a d i f f e r e n t b e h a v i o u r a l t e c h n i q u e . The t e c h n i q u e used i n the p r e s e n t experiment was a m o d i f i c a t i o n of the hot p l a t e p a w - l i c k jump-escape t e s t f o r a n a l g e s i a ( e . g . Amir & Amit,1978; A n k i e r , 1 9 7 4 ; Bardo & Hughes, 1979; G l i c k , 1976). When r a t s a re p l a c e d on a hot s u r f a c e ( a p p r o x i m a t e l y 50-55° C ) , they e x h i b i t a t l e a s t two c h a r a c t e r i s t i c b e h a v i o u r s i n te m p o r a l sequence. A f t e r some time on the hot s u r f a c e , the r a t w i l l b e g i n t o l i c k and m a n i p u l a t e the v e n t r a l s u r f a c e of the paws t h a t have been i n c o n t a c t w i t h the s u r f a c e . The l a t e n c y t o the f i r s t paw l i c k i s the u s u a l measure (Amir & Amit, 1978). E v e n t u a l l y the r a t w i l l jump from the f l o o r of the h o t - p l a t e a p p a r a t u s and the l a t e n c y t o the f i r s t jump-escape response t y p i c a l l y c o n s t i t u t e s the second measure. The purpose of the p r e s e n t experiment t h e n , was t o demonstrate the g e n e r a l i t y of the a n t i n o c i c e p t i v e e f f e c t of abnormal motion u s i n g a d i f f e r e n t t e s t of a n t i n o c i c e p t i o n , the hot p l a t e p a w - l i c k jump-escape t e s t . METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 20 n a i v e male hooded r a t s w e i g h i n g a p p r o x i m a t e l y 350 gm. The s u b j e c t s were p u r c h a s e d , housed, and m a i n t a i n e d as p r e v i o u s l y d e s c r i b e d . A p p a r a t u s The hot p l a t e a p p a r a t u s c o n s i s t e d of an open-topped P l e x i g l a s box (15 X 19.5 X 41 cm). The bottom of the box was 44 c o n s t r u c t e d of t h i n sheet metal and a l l seams were s e a l e d w i t h s i l i c o n e s e a l a n t . In use, the P l e x i g l a s box r e s t e d on two wooden s u p p o r t s i n a c o n s t a n t temperature (55° C) water bath (B l u e M) w i t h the m e t a l f l o o r a t a depth of 1 cm i n the water b a t h . The use of a c o n s t a n t temperature water b a t h as a heat source r a t h e r than the u s u a l e l e c t r i c h o t - p l a t e e n s u r e d even heat d i s t r i b u t i o n over the e n t i r e f l o o r . The metal f l o o r of the a p p a r a t u s was c l e a n e d and d r i e d a f t e r each use. P r o c e d u r e On each of the 2 days p r i o r t o t e s t i n g , a l l s u b j e c t s were a c c l i m a t e d t o the r e s t r a i n i n g tubes f o r 5 min and t o the non-f u n c t i o n a l hot p l a t e a p p a r a t u s f o r a n o t h e r 5 min. On the day of t e s t i n g , s u b j e c t s were randomly a s s i g n e d t o e i t h e r the motion or r e s t r a i n t c o n d i t i o n s . The abnormal motion t r e a t m e n t was i d e n t i c a l t o the combined h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n t r e a t m e n t s used i n E x p e r i m e n t s 2 and 3. R a t s i n the r e s t r a i n t c o n d i t i o n were merely p l a c e d i n the r e s t r a i n i n g tubes f o r the 5 min p e r i o d . Immediately f o l l o w i n g the e x p i r a t i o n of the 5 min t r e a t m e n t p e r i o d , the r a t was withdrawn from the r e s t r a i n i n g tube and p l a c e d i n the now f u n c t i o n a l hot p l a t e a p p a r a t u s . L a t e n c y t o the f i r s t p a w - l i c k response was r e c o r d e d on one t i m e r , and l a t e n c y t o the f i r s t jump-escape response t h a t c o m p l e t e l y c l e a r e d the f l o o r of the a p p a r a t u s was r e c o r d e d on the second t i m e r . The r a t s were removed from the a p p a r a t u s upon c o m p l e t i o n of the jump-escape response or when 200 sec had e x p i r e d w i t h o u t a s u c c e s s f u l jump-escape response. T h i s maximum was imposed t o p r e v e n t p o s s i b l e t i s s u e damage from s u s t a i n e d exposure t o the t h e r m a l s t i m u l u s . 45 RESULTS AND DISCUSSION The p a w - l i c k and jump-escape l a t e n c i e s a r e i l l u s t r a t e d i n F i g u r e 6. There was a s i g n i f i c a n t d i f f e r e n c e between motion and r e s t r a i n t c o n d i t i o n s i n the l a t e n c y t o p a w - l i c k (t=3.66, df=16, p<.05) but d i f f e r e n c e s i n the jump-escape measure were not s i g n i f i c a n t (t=.73, df=16, p>.05). I f one c o n s i d e r s o n l y the p a w - l i c k r e sponse, i t i s c l e a r t h a t exposure t o abnormal motion produces an a n a l g e s i c e f f e c t . The f a i l u r e t o f i n d an a n t i n o c i c e p t i v e e f f e c t i n the jump-escape measure i s somewhat more d i f f i c u l t t o i n t e r p r e t . I t may be t h a t t h i s measure i s merely l e s s s e n s i t i v e than the p a w - l i c k response i n a s s e s s i n g the p r e s e n c e or absence of a n t i n o c i c e p t i o n , or the two responses may w e l l r e f l e c t d i f f e r e n t u n d e r l y i n g mechanisms. Amit and Amir (1978) f o r example, suggest t h a t the p a w - l i c k response r e f l e c t s the s e n s o r y components of p a i n p e r c e p t i o n , whereas the jump-escape response r e f l e c t s the a f f e c t i v e component of p a i n p e r c e p t i o n . I f t h i s i s t r u e , one c o u l d perhaps argue t h a t the a n t i n o c i c e p t i v e a c t i v i t y of abnormal motion e x e r t s i t s e f f e c t s p r i m a r i l y on the s e n s o r y components of n o c i c e p t i o n . I t i s a l s o p o s s i b l e t h a t t h e l a c k of d i f f e r e n c e i n the jump-escape measure may be e x p l a i n e d by an a t t e n u a t i o n of the a n a l g e s i c e f f e c t of abnormal motion w i t h t i m e . P a w - l i c k l a t e n c i e s were about 10 s e c , whereas jump-escape l a t e n c i e s were about 100 s e c . I t i s p o s s i b l e t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion d e t e c t e d by the p a w - l i c k response c o u l d have d e c l i n e d over the subsequent 90 s e c . A c c o r d i n g l y , Experiment 5 was d e s i g n e d t o p r o v i d e i n f o r m a t i o n c o n c e r n i n g the d u r a t i o n of the a n t i n o c i c e p t i v e e f f e c t of the combined h o r i z o n t a l r o t a t i o n 46 FIGURE 6. R e s u l t s of a n a l g e s i a t e s t i n g i n Experiment 4. MOT r e f e r s t o the abnormal motion t r e a t m e n t w h i l e REST r e f e r s t o the r e s t r a i n t c o n t r o l t r e a t m e n t . PAW LICK LATENCY MOT REST ESCAPE LATENCY 48 and v e r t i c a l o s c i l l a t i o n motion s t i m u l u s used i n t h i s and p r e v i o u s e x p e r i m e n t s . Experiment 5 Experiment 5 was d e s i g n e d t o a s s e s s the d u r a t i o n of the a n t i n o c i c e p t i v e e f f e c t s produced by d i f f e r e n t p e r i o d s of exposure t o combined h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n . METHOD S u b j e c t s The s u b j e c t s were 64 male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 350 gm, o b t a i n e d and m a i n t a i n e d as d e s c r i b e d p r e v i o u s l y . P r o c e d u r e On each of the t h r e e days p r i o r t o t e s t i n g , a l l a n i m a l s were a c c l i m a t e d t o the r e s t r a i n i n g tubes f o r a 5 min p e r i o d . On the day of t e s t i n g , e i g h t a n i m a l s were randomly a s s i g n e d t o each of f o u r motion d u r a t i o n s , 5 s e c , 30 s e c , 300 s e c , or 900 s e c , and t o each of f o u r e q u i v a l e n t d u r a t i o n r e s t r a i n t c o n d i t i o n s . Immediately f o l l o w i n g the e x p i r a t i o n of the motion or r e s t r a i n t t r e a t m e n t , the u s u a l hot-water t a i l w i t h d r a w a l t e s t f o r a n a l g e s i a was conducted (0 min t e s t ) . A s e r i e s of subsequent t e s t s were conducted 1 min, 3 min, 10 min, and 30 min f o l l o w i n g t e r m i n a t i o n of the t r e a t m e n t c o n d i t i o n . A l l r a t s remained i n the r e s t r a i n i n g tubes throughout the a n a l g e s i a t e s t i n g . i n o r d e r t o e l i m i n a t e p o s s i b l e undue e f f e c t s a t t r i b u t a b l e t o r e p e a t e d h a n d l i n g . The d e s i g n of the experiment t h e n , was a 2 X 4 X 5 r e p e a t e d measures. 49 R a t s were t e s t e d i n p a i r s , each p a i r c o n s i s t i n g of one r a t from one of the f o u r motion c o n d i t i o n s and the o t h e r from the e q u i v a l e n t d u r a t i o n r e s t r a i n t o n l y c o n d i t i o n . The r e s t r a i n t o n l y c o n d i t i o n of the p a i r was begun a p p r o x i m a t e l y 30 sec f o l l o w i n g i n i t i a t i o n of the motion c o n d i t i o n so t h a t a n a l g e s i a t e s t i n g c o u l d be conducted a t the a p p r o p r i a t e i n t e r v a l s w i t h o u t c o n f l i c t . T e s t i n g was completed over s e s s i o n s on f o u r c o n s e c u t i v e a f t e r n o o n s w i t h one q u a r t e r of the r a t s from each t r e a t m e n t c o n d i t i o n (n = 16) t e s t e d on each of the 4 days. RESULTS The r e s u l t s of Experiment 5 a g a i n c o n f i r m the e x i s t e n c e of an a n t i n o c i c e p t i v e e f f e c t of abnormal motion (see F i g u r e 7 ) . A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t a n a l g e s i c e f f e c t of motion (F=10.50, d f = l / 5 6 , p<.05). The e f f e c t of d i f f e r e n t motion d u r a t i o n s d i d not r e a c h s i g n i f i c a n c e (F=2.12, df=3/56, p>.05) i n the o v e r a l l a n a l y s i s , but the motion t r e a t m e n t by d u r a t i o n of motion i n t e r a c t i o n was s i g n i f i c a n t (F=2.98, df=3/56, p<.05). Post-hoc a n a l y s i s (Tukey) i n d i c a t e d t h a t t a i l w i t h d a w a l l a t e n c i e s i n the f o u r r e s t r a i n t groups and the 5 and 30 sec motion exposure groups were not s i g n i f i c a n t l y d i f f e r e n t (p>.05). A n a l y s i s of main e f f e c t s ( K e p p l e , 1973) i n d i c a t e d t h a t the a n a l g e s i c e f f e c t of abnormal motion was s i g n i f i c a n t i n the 300 and 900 sec motion d u r a t i o n c o n d i t i o n s (F=10.97, d f = l / 5 6 , p<.05; F=7.90, d f = l / 5 6 , p<.05, r e s p e c t i v e l y ) but not i n the 5 and 30 sec groups (see F i g u r e 7 ) . The o v e r a l l a n a l y s i s of v a r i a n c e a l s o i n d i c a t e d a s i g n i f i c a n t o v e r a l l d e c l i n e i n t a i l w i t h d r a w a l l a t e n c i e s over r e p e a t e d t e s t s (F=36.53, df=4/224, p<.05) and a s i g n i f i c a n t 50 FIGURE 7. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s exposed t o 5-, 30-, 300-, or 900-sec p e r i o d s of the abnormal motion t r e a t m e n t used i n Experiment 5. Time of t e s t r e f e r s t o t h e t i m e s a t which r e p e a t e d a n a l g e s i a t e s t s were a d m i n i s t e r e d a f t e r t e r m i n a t i o n of the motion or r e s t r a i n t t r e a t m e n t . TIME OF TEST (MIN) 52 d u r a t i o n of exposure by r e p e a t e d t e s t s i n t e r a c t i o n (F=2.04, df=12/224, p<.05). N e i t h e r the motion c o n d i t i o n by r e p e a t e d t e s t s i n t e r a c t i o n nor the three-way i n t e r a c t i o n term reached s i g n i f i c a n c e . A p r i o r i c omparisons ( t - t e s t ) of the motion and r e s t r a i n t c o n d i t i o n s a t the v a r i o u s t e s t i n t e r v a l s i n d i c a t e d t h a t motion produced a s i g n i f i c a n t e l e v a t i o n i n t a i l w i t h d r a w a l l a t e n c i e s (p<.05) at the 0, 1, and 10 min t e s t i n t e r v a l s i n the 900 sec motion d u r a t i o n c o n d i t i o n (t=3.88, df=14; t=2.68, df=14; t=2.55, df=14; r e s p e c t i v e l y ) . In the 300 sec motion d u r a t i o n c o n d i t i o n , motion produced a s i g n i f i c a n t e l e v a t i o n i n t a i l w i t h d r a w a l l a t e n c i e s (p<.05) i n the 0, 1, 3, and 10 min motion c o n d i t i o n s (t=2.53, df=14; t=3.82, df=14; t=2.27, df=14; t=2.50, df=14). No s i g n i f i c a n t changes i n t a i l w i t h d r a w a l l a t e n c i e s were found a t any t e s t i n t e r v a l i n the 5 and 30 sec motion d u r a t i o n c o n d i t i o n s . DISCUSSION Experiment 5 not o n l y p r o v i d e s a d d i t i o n a l c o n f i r m a t i o n of an a n t i n o c i c e p t i v e e f f e c t r e s u l t i n g from exposure t o abnormal motion c o n d i t i o n s i n r a t s but a l s o p r o v i d e s a d d i t i o n a l i n f o r m a t i o n c o n c e r n i n g the exposure time n e c e s s a r y t o e l i c i t the phenomenon and the d u r a t i o n of the a n a l g e s i a once e l i c i t e d . The p r e s e n t r e s u l t s suggest t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion does not appear i n s t a n t a n e o u s l y upon i n i t i a t i o n of the abnormal motion regimen but r e q u i r e s between 30 and 300 sec t o d e v e l o p w i t h the type of motion used h e r e . I t a l s o appears t h a t the a n a l g e s i a e l i c i t e d by t h i s motion reaches some a s y m p t o t i c l e v e l and does not i n c r e a s e s i g n i f i c a n t l y w i t h f u r t h e r exposure (300 t o 900 s e c ) . A s i m i l a r a s y m p t o t i c l e v e l 53 of a n a l g e s i a was a l s o found i n Experiment 1, i n which a s w i n g i n g motion was the p r o v o c a t i v e s t i m u l u s . I t i s not known however, i f the t r a n s i t i o n from a s t a t e of no a n a l g e s i a t o f u l l blown a n a l g e s i a w i t h i n c r e a s i n g motion exposure d u r a t i o n i s a smooth g r a d u a l f u n c t i o n or r e p r e s e n t s an a b r u p t t r a n s i t i o n . T h i s q u e s t i o n c o u l d p o s s i b l y be answered w i t h the use of more t e s t i n g i n t e r v a l s between the 30- and 300-sec a n a l g e s i a t e s t i n t e r v a l s used h e r e . The f a c t t h a t a 5- or 30-sec exposure t o abnormal motion f a i l s t o e l i c i t a n a l g e s i a s u g g e s t s t h a t the a n a l g e s i a e l i c i t e d by l o n g e r exposure d u r a t i o n s i s not produced by ' f e a r ' or ' s u r p r i s e ' elements of the abnormal m o t i o n . I f th e s e f a c t o r s were o p e r a t i n g i n the a n t i n o c i c e p t i v e e f f e c t seen h e r e , one would e x p e c t t h e i r e f f e c t t o be maximal near the b e g i n n i n g of the exposure p e r i o d . I t a l s o appears t h a t the a n t i n o c i c e p t i v e e f f e c t decays g r a d u a l l y w i t h time from t e r m i n a t i o n of the abnormal m o t i o n , a t l e a s t i n r e p e a t e d t e s t s . T h i s decay i n the s t r e n g t h of the a n t i n o c i c e p t i v e e f f e c t i s almost c e r t a i n l y not an a r t i f a c t of the r e p e a t e d t e s t i n g p r o c e d u r e . C o n t r o l r a t s exposed o n l y t o r e s t r a i n t f o r p e r i o d s of up t o 45 min demonstrated r e m a r k a b l y s t a b l e t a i l w i t h d r a w a l l a t e n c i e s over time and r e p e a t e d t e s t s . I f r e p e a t e d t e s t i n g were a f a c t o r i n the decay of the a n t i n o c i c e p t i v e e f f e c t , a s i m i l a r d e c l i n e i n t a i l w i t h d r a w a l l a t e n c i e s s h o u l d have been shown i n the c o n t r o l a n i m a l s exposed t o r e s t r a i n t o n l y . 54 G e n e r a l D i s c u s s i o n -_' S e c t i o n I_ The p r e c e d i n g f i v e e x p e r i m e n t s demonstrated the e x i s t e n c e of an a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n r a t s . The a n t i n o c i c e p t i v e e f f e c t was r o b u s t , p r o d u c i n g i n c r e a s e s of 35 t o 100% i n two d i f f e r e n t a s s a y s of a n a l g e s i a . I t a l s o seems t h a t once exposure t o an abnormal motion environment i s i n i t i a t e d , the exposure must c o n t i n u e f o r some p e r i o d of time b e f o r e f u l l e x p r e s s i o n of the a n t i n o c i c e p t i v e e f f e c t i s a c h i e v e d . T h i s l a g i n the onset of the b e h a v i o u r a l e f f e c t f o l l o w i n g onset of the motion s t i m u l u s i s s i m i l a r t o the development of o t h e r b e h a v i o u r a l e f f e c t s of abnormal m o t i o n . M o t i o n s i c k n e s s , f o r example, does not g e n e r a l l y appear i m m e d i a t e l y f o l l o w i n g onset of the motion s t i m u l u s but s i g n s and symptoms d e v e l o p p r o g r e s s i v e l y as s t i m u l u s exposure p r o c e e d s (Reason & G r a y b i e l , 1970) . In a d d i t i o n , i t appears t h a t t h e r e i s an a s y m p t o t i c degree of a n a l g e s i a t h a t may be e l i c i t e d by the p a r t i c u l a r motion s t i m u l i of the p r e s e n t e x p e r i m e n t s . P e r c e n t a g e comparisons of the s w i n g i n g motion and the combined h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n motion t o t h e i r r e s p e c t i v e c o n t r o l s ( s w i n g i n g - 85% g r e a t e r than c o n t r o l s , r o t a t i o n and o s c i l l a t i o n - 35% g r e a t e r than c o n t r o l s ) , s u g g e s t s t h a t t h i s a s y m p t o t i c l e v e l of a n a l g e s i a may d i f f e r depending on the type of motion used t o e l i c i t t h e a n t i n o c i c e p t i v e e f f e c t . The degree of the a n t i n o c i c e p t i v e e f f e c t appears t o depend on the form of the motion s t i m u l u s used. I n . t h e p r e c e d i n g e x p e r i m e n t s , complex motions ( i . e . , s w i n g i n g or r o t a t i o n and o s c i l l a t i o n ) were more e f f e c t i v e than r e l a t i v e l y l e s s complex 55 forms of motion ( i e . r o t a t i o n or v e r t i c a l o s c i l l a t i o n ) . I f the a n t i n o c i c e p t i v e e f f e c t i s dependent on abnormal v e s t i b u l a r s t i m u l a t i o n , i t i s not u n r e a s o n a b l e t o suggest t h a t complex abnormal motions such as s w i n g i n g or h o r i z o n t a l r o t a t i o n combined w i t h v e r t i c a l o s c i l l a t i o n would have more impact on more components of the v e s t i b u l a r system and hence produce g r e a t e r o v e r a l l v e s t i b u l a r a c t i v i t y than would r e l a t i v e l y s i m p l e forms of v e s t i b u l a r s t i m u l a t i o n . Other e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n such as motion s i c k n e s s a r e a l s o more e a s i l y e l i c i t e d by r e l a t i v e l y complex forms of abnormal motion (Reason & Brand, 1975). A l t h o u g h t h e r e i s a decrement i n the r e s p o n s i v e n e s s of r a t s t o n o x i o u s or p a i n f u l s t i m u l i f o l l o w i n g a p e r i o d of abnormal m o t i o n , t h e r e a r e a number of i s s u e s t h a t may have a b e a r i n g on the g e n e r a l i t y and u s e f u l n e s s of t h i s e f f e c t . Such i s s u e s as the v a l i d i t y of the use of r e s t r a i n t as the a p p r o p r i a t e c o n t r o l c o n d i t i o n , the p o s s i b i l i t y of unnecessary e r r o r i n t r o d u c e d by the t e c h n i q u e used t o measure l a t e n c i e s , and the g e n e r a l i z a b i l i t y of the phenomenon a r e d i s c u s s e d i n the f o l l o w i n g p a r a g r a p h s . I t i s p o s s i b l e t h a t the magnitude of the a n t i n o c i c e p t i v e e f f e c t d e s c r i b e d here i s somehow a f f e c t e d by the use of an i n a p p r o p r i a t e c o n t r o l c o n d i t i o n . That i s , the use of r e s t r a i n t as the c o n t r o l c o n d i t i o n may have perhaps masked or e x a g g e r a t e d the e f f e c t s of abnormal motion by e i t h e r i n c r e a s i n g or d e c r e a s i n g the b a s e l i n e a n a l g e s i a measures. For example, Amir and Amit (1978) have shown t h a t a s i g n i f i c a n t amount of a n a l g e s i a can be induced by c o m p l e t e l y i m m o b i l i z i n g r a t s f o r 56 o p e r i o d s of t i m e . T h i s i m m o b i l i z a t i o n - i n d u c e d a n a l g e s i a may a l s o e x p l a i n the a n t i n o c i c e p t i v e / e f f e c t s of e x p o s i n g r a t s t o r a d i a l a c c e l e r a t i o n s of 7G (Hayes, Bennet, Newlon, & Mayer, 1978). I t must be remembered t h a t the r e s t r a i n i n g system used here i n no way ' i m m o b i l i z e d ' the r a t but d i d r e s t r i c t the range of movements a v a i l a b l e t o the a n i m a l . S t u d i e s i n our l a b o r a t o r y i n d i c a t e d t h a t t a i l w i t h d r a w a l l a t e n c i e s d i d not d i f f e r between n o n - r e s t r a i n e d r a t s and r a t s s u b j e c t e d t o 5 min of r e s t r a i n t (X = 4.05 s e c , s.d.= 1.45; X = 4.30 s e c , s.d. = 1.81, r e s p e c t i v e l y ) . Because l a t e n c i e s d i d not change n o t i c e a b l y w i t h i n c r e a s i n g p e r i o d s of r e s t r a i n t (up t o 45 m i n ) , the r e s u l t s of Experiment 5 a l s o suggest t h a t the r e s t r a i n t c o n d i t i o n i t s e l f has l i t t l e e f f e c t on t a i l - w i t h d r a w a l l a t e n c i e s . I t i s a l s o p o s s i b l e t h a t the p r e s e n t s t u d i e s c o u l d be c r i t i c i z e d w i t h r e s p e c t t o the t e c h n i q u e used t o measure t a i l w i t h d r a w a l l a t e n c i e s . , the p r i m a r y measure of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . A l t h o u g h i t i s perhaps t r u e t h a t human o b s e r v e r s o p e r a t i n g e l e c t r o n i c stopwatches a r e s u s c e p t i b l e t o o b s e r v e r b i a s e s , r e a c t i o n time d e f i c i t s , and o t h e r s u b t l e forms of d a t a a q u i s i t i o n e r r o r s , t h e s e f a c t o r s d i d not appear t o p r e s e n t d i f f i c u l t i e s i n the p r e s e n t e x p e r i m e n t s . A p a i d o b s e r v e r was used t o r e c o r d t a i l w i t h d r a w a l l a t e n c i e s i n many of the e x p e r i m e n t s and the r e l i a b i l i t y of the human measurement t e c h n i q u e was examined by two d i f f e r e n t methods. F i r s t , an i n t e r - o b s e r v e r r e l i a b i l i t y c o e f f i c i e n t was c a l c u l a t e d between two independent o b s e r v e r s and r e s u l t e d i n a c o r r e l a t i o n of .995 (Pearson product-moment). Second, l a t e n c y measures o b t a i n e d w i t h the use of an e l e c t r o n i c d e v i c e ( S k e l t o n & Gray, 57 u n p u b l i s h e d m a n u s c r i p t , 1980) were compared t o l a t e n c i e s o b t a i n e d by a human o b s e r v e r u s i n g the stopwatch method. A c o r r e l a t i o n of .975 (Pearson product-moment) r e s u l t e d from t h i s c o m p a r i s o n . The e l e c t r o n i c d e v i c e was not used i n subsequent t e s t s because i t was s u s c e p t i b l e t o an o c c a s i o n a l f a i l u r e , which r e s u l t e d i n a l o s s of d a t a . The f i n a l i s s u e c o n c e r n s the g e n e r a l i z a b i l i t y of the a n t i n o c i c e p t i v e e f f e c t and the p o t e n t i a l u s e f u l n e s s of abnormal motion as a means of n o n - p h a r m a c o l o g i c a l p a i n c o n t r o l i n humans. The e x c l u s i v e use of male r a t s i n the p r e c e d i n g s t u d i e s may t e n d t o r e s t r i c t the g e n e r a l i t y of the a n t i n o c i c e p t i v e e f f e c t somewhat. A l t h o u g h female r a t s have been found i n our l a b o r a t o r y t o e x h i b i t mot i o n - i n d u c e d a n a l g e s i a i d e n t i c a l t h a t d i s p l a y e d by male r a t s , the g e n e r a l i t y of t h i s phenomenon a c r o s s s p e c i e s has not y e t been e s t a b l i s h e d . I t seems l i k e l y however, t h a t t h i s g e n e r a l i t y e x i s t s as o t h e r b e h a v i o u r a l e f f e c t s of abnormal motion ( e . g . , motion s i c k n e s s , d r o w s i n e s s ) demonstrate wide g e n e r a l i t y a c r o s s s p e c i e s . Dogs, c a t s , monkeys, and o t h e r a n i m a l s a l l demonstrate motion s i c k n e s s and d r o w s i n e s s upon exposure t o a p p r o p r i a t e forms of abnormal motion ( B r i z z e e , Ordy, & M e h l e r , 1980; Money, 1970; S u r i , Crampton, & Daunton, 1979). The r e l a t i v e l y s h o r t d u r a t i o n of a n a l g e s i a f o l l o w i n g abnormal motion i n r a t s would seem, a t f i r s t g l a n c e , t o r e s t r i c t the u s e f u l n e s s of the t e c h n i q u e f o r p a i n c o n t r o l i n humans. I t appears however, t h a t the d u r a t i o n of a n a l g e s i a produced by n o n p h a r m a c o l o g i c a l methods i n r a t s does not a c c u r a t e l y p r e d i c t the d u r a t i o n of a n a l g e s i a produced by the same methods i n humans. Transcutaneous e l e c t r i c shock f o r example, may produce 58 l o n g - l a s t i n g and even permanent r e l i e f from p a i n i n human p a t i e n t s s u f f e r i n g from c h r o n i c p a i n (Melzack & D e n n i s , 1978), whereas the same t e c h n i q u e produces r e l a t i v e l y s h o r t p e r i o d s of a n a l g e s i a i n the r a t (Hayes, Bennet, Newlon, & Mayer, 1978). T h i s same d i s p a r i t y between e x p e r i m e n t a l r e s u l t s i n a n i m a l s and c l i n i c a l e f f i c a c y i n humans may w e l l e x i s t f o r a n a l g e s i a produced by abnormal motion. I f t h i s were t r u e , abnormal motion would seem t o o f f e r some advantages over o t h e r forms of n o n p h a r m a c o l o g i c a l p a i n c o n t r o l such as t r a n s c u t a n e o u s e l e c t r i c a l s t i m u l a t i o n , a c u p u n c t u r e , and e l e c t r i c a l s t i m u l a t i o n . I t i s easy t o a d m i n i s t e r , not p a i n f u l f o r the p a t i e n t , has no r i s k of i n f e c t i o n or t i s s u e damage, and r e q u i r e s no s u r g i c a l p r e p a r a t i o n of the p a t i e n t . As y e t however, t h e r e has been no e m p i r i c a l t e s t of a n t i n o c i c e p t i v e responses t o abnormal motion i n humans. 59 SECTION I I - V e s t i b u l a r M e d i a t i o n of the A n t i n o c i c e p t i v e Phenomenon I t has been assumed i n the p r e c e d i n g d i s c u s s i o n s t h a t the v e s t i b u l a r system i s the p r i m a r y m e d i a t o r of the a n t i n o c i c e p t i v e e f f e c t s of abnormal m o t i o n . A l t h o u g h t h i s assumption may have some i n t u i t i v e v a l i d i t y based on the p r i m a r y sensory r o l e of the v e s t i b u l a r system i n d e t e c t i n g motion ( e . g . , B r o d a l , Pompeiano, & Walberg; G o l d s t e i n , 1974), i t i s a l s o p o s s i b l e t h a t o t h e r s e n s o r y mechanisms such as the v i s u a l and k i n e s t h e t i c senses p l a y an i m p o r t a n t r o l e i n the n e u r a l m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . The e x p e r i m e n t s d i s c u s s e d below i n S e c t i o n I I were e x p l i c i t l y d e s i g n e d t o t e s t the h y p o t h e s i s t h a t the v e s t i b u l a r system i s an e s s e n t i a l component of the n e u r a l m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal motion and t o f u r t h e r e x p l o r e the r o l e of the v e s t i b u l a r system i n t h i s e f f e c t . P r e v i o u s i n v e s t i g a t i o n s of the r o l e of t h e v e s t i b u l a r system i n m e d i a t i n g o t h e r b e h a v i o u r a l e f f e c t s of abnormal m o t i o n , a l t h o u g h few, have s u g g e s t e d t h a t an i n t a c t v e s t i b u l a r system i s e s s e n t i a l f o r the appearance of such e f f e c t s as motion s i c k n e s s and d r o w s i n e s s . L a b y r i n t h i n e d e f e c t i v e human s u b j e c t s , f o r example, a r e i n s e n s i t i v e t o the i l l n e s s - i n d u c i n g and s o p o r i f i c p r o p e r t i e s of abnormal motion ( G r a y b i e l , 1965; Johnson & Jongkees, 1974). Dogs w i t h l e s i o n s of v a r i o u s p o r t i o n s of the v e s t i b u l a r system, i n c l u d i n g p e r i p h e r a l and c e n t r a l components, a l s o appear immune t o the i l l n e s s - i n d u c i n g p r o p e r t i e s of abnormal motion (Money, 1970; Money & F r i e d b e r g , 1964). Moreover, r a t s w i t h l e s i o n s of the p e r i p h e r a l v e s t i b u l a r 60 a p p a r a t u s do not d e v e l o p a v e r s i o n s t o a n o v e l f l u i d p a i r e d w i t h exposure t o abnormal motion ( H a r o u t u n i a n , R i c c i o , & Gans, 1976). S e c t i o n I I of the p r e s e n t t h e s i s , c o n s i s t s of t h r e e e x p e r i m e n t s d i r e c t e d a t e x p l o r i n g the r o l e of the v e s t i b u l a r system i n m e d i a t i n g the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . Experiment 6 i n v e s t i g a t e d the e f f e c t of l e s i o n i n g the p e r i p h e r a l r e c e p t o r o r g a n s , whereas E x p e r i m e n t s 7 and 8 used d i s c r e t e l e s i o n and e l e c t r i c a l s t i m u l a t i o n t e c h n i q u e s r e s p e c t i v e l y , t o e x p l o r e the r o l e of some c e n t r a l nervous system components of the v e s t i b u l a r system. Experiment 6 The purpose of Experiment 6 was t o i n v e s t i g a t e the p o s s i b l e e f f e c t s of a d y s f u n c t i o n a l v e s t i b u l a r system on the a n t i n o c i c e p t i v e e f f e c t s of abnormal . m o t i o n . T h i s was a c c o m p l i s h e d by d e s t r o y i n g p o r t i o n s of the p e r i p h e r a l r e c e p t o r o r g a n s , th u s d i s r u p t i n g i n p u t from the r e c e p t o r organs t o the c e n t r a l v e s t i b u l a r system. I f an i n t a c t v e s t i b u l a r system i s n e c e s s a r y f o r the e x p r e s s i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n , then d i s r u p t i o n of v e s t i b u l a r i n p u t s h o u l d e l i m i n a t e or a t t e n u a t e the a n t i n o c i c e p t i v e phenomenon. METHOD S u b j e c t s and S urgery The s u b j e c t s were 30 male hooded r a t s w e i g h i n g a p p r o x i m a t e l y 300 gm a t the time of s u r g e r y . S u b j e c t s were p u r c h a s e d , housed, and m a i n t a i n e d as d e s c r i b e d p r e v i o u s l y . The g e n e r a l s u r g i c a l p r o c e d u r e i n v o l v e d a t r a n s a u r i c u l a r approach t o the p e r i p h e r a l v e s t i b u l a r r e c e p t o r organs t h r o u g h 61 the o v a l window, f o l l o w e d by a r a d i o - f r e q u e n c y produced l e s i o n i n the i n n e r e a r . These l e s i o n s e f f e c t i v e l y e l i m i n a t e the a b i l i t y of the i n n e r ear v e s t i b u l a r s t r u c t u r e s t o respond t o a c c e l e r a t i v e s t i m u l i i n a normal manner. T h i s g e n e r a l p r o c e d u r e i s i d e n t i c a l t o the proc e d u r e used by P o t e g a l , Abraham, Gilman, and Copak (1975) and H a r o u t u n i a n , R i c c i o , and Gans (1976) t o produce d e a f f e r e n t a t i o n of the v e s t i b u l a r system. A l l r a t s were a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l (Nembutal, 50 mg/kg, i . p . ) and a s s i g n e d t o one of t h r e e l e s i o n groups: a v e s t i b u l a r - d a m a g e d group (n = 1 2 ) , an o p e r a t e d - c o n t r o l group (n = 1 2 ) , or an a n e s t h e t i z e d - c o n t r o l group (n = 1 2 ) . In t h e v e s t i b u l a r damaged group, a s m a l l c u t was made a n t e r i o r t o the t r a g u s t o a l l o w f u l l v i s u a l i z a t i o n of the a u d i t o r y meatus and the tympanic membrane. The a u d i t o r y meatus was h e l d open w i t h a p a i r of f i n e f o r c e p s and, w i t h the a i d of a 25-power s u r g i c a l m i c r o s c o p e ( Z e i s s ) , the tympanic membrane was p u n c t u r e d and p e e l e d away w i t h a 23 ga s t a n d a r d b e v e l hypodermic needle ( B e c t o n - D i c k i n s o n , d i s p o s a b l e ) . The m a l l e u s and i n c u s were then g e n t l y p r i e d from t h e i r p o s i t i o n s and the f o o t p l a t e of the s t a p e s v i s u a l i z e d . The s t a p e s f o o t p l a t e was then g e n t l y p r i e d from i t s p o s i t i o n on the o v a l window. G r e a t c a r e was tak e n not t o i n j u r e the p t e r y g o p a l i t i n e a r t e r y which l i e s d i r e c t l y above the f o o t p l a t e and t h r o u g h the ' s t i r r u p ' p o r t i o n of the s t a p e s . I f t h i s a r t e r y was damaged, p r o f u s e b l e e d i n g ensued and the s u r g i c a l p r o c e d u r e was t e r m i n a t e d . A s t a i n l e s s s t e e l , i n s u l a t e d . e l e c t r o d e ( s i z e '00' i n s e c t p i n ) was then i n s e r t e d i n the o v a l window t o a depth of a p p r o x i m a t e l y 2 mm and the r a d i o f r e q u e n c y c u r r e n t passed t h r o u g h the e l e c t r o d e and an 62 a n a l ground e l e c t r o d e . Radio f r e q u e n c y c u r r e n t was g e n e r a t e d by a Grass RF-4 l e s i o n g e n e r a t o r and c u r r e n t parameters were an i n d i c a t e d 20 mA f o r a 20-sec p e r i o d . The e l e c t r o d e was then removed and the proce d u r e was r e p e a t e d on the c o n t r a l a t e r a l s i d e . The e n t i r e p r o c e d u r e r e q u i r e d a p p r o x i m a t e l y 20 min per s u b j e c t f o r c o m p l e t i o n . S u r g i c a l p r o c e d u r e s were i d e n t i c a l f o r the o p e r a t e d c o n t r o l group except t h a t the pr o c e d u r e was t e r m i n a t e d when the s t a p e s f o o t p l a t e had been v i s u a l i z e d and moved s l i g h t l y . As b o th the o p e r a t e d c o n t r o l group and the v e s t i b u l a r damaged group were made deaf i n the c o u r s e of the s u r g i c a l p r o c e d u r e , an a d d i t i o n a l group of r a t s was i n c l u d e d t o c o n t r o l f o r the p o s s i b l e c o n f o u n d i n g e f f e c t s of d e a f n e s s . T h i s a d d i t i o n a l group, the a n e s t h e t i z e d c o n t r o l group, was a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l and a l l o w e d t o r e c o v e r from the a n e s t h e t i c w i t h no f u r t h e r s u r g i c a l i n t e r v e n t i o n . F o l l o w i n g s u r g e r y , a l l a n i m a l s were housed i n groups c o n s i s t i n g of s i x a n i m a l s from the same s u r g i c a l c o n d i t i o n s . Two a n i m a l s from the v e s t i b u l a r l e s i o n group and one from the o p e r a t e d c o n t r o l group d i e d i n the i n t e r v a l between s u r g e r y and t e s t i n g , r e d u c i n g group s i z e s a c c o r d i n g l y . Food and water were f r e e l y a v a i l a b l e and a d d i t i o n a l f o o d p e l l e t s were p l a c e d d a i l y on the f l o o r s of a l l cages. A 14-day r e c o v e r y p e r i o d was a l l o w e d between s u r g e r y and b e h a v i o u r a l t e s t i n g . P r o c e d u r e On each of t h r e e days p r i o r t o t e s t i n g , a l l r a t s were i n d i v i d u a l l y h a b i t u a t e d t o the r e s t r a i n i n g tubes f o r a 5-min p e r i o d . On the t e s t day, f i v e r a t s from each s u r g i c a l group 63 were randomly a s s i g n e d t o the motion c o n d i t i o n , and the r e m a i n i n g f i v e were a s s i g n e d t o the r e s t r a i n t - o n l y c o n d i t i o n . The motion used i n the p r e s e n t experiment was the s w i n g i n g motion d e s c r i b e d i n Experiment 1. Two r a t s from each s u r g i c a l c o n d i t i o n were t e s t e d s i m u l t a n e o u s l y , one r a t i n the motion c o n d i t i o n and the o t h e r i n the r e s t r a i n t c o n d i t i o n . Immediately f o l l o w i n g the t e r m i n a t i o n of the motion or r e s t r a i n t t r e a t m e n t , a h o t - w a t e r t a i l w i t h d r a w a l a n a l g e s i a t e s t was a d m i n i s t e r e d (Test 1) u s i n g the same a p p a r a t u s and p r o c e d u r e s d e s c r i b e d e a r l i e r . On the f o l l o w i n g day, a second a n a l g e s i a t e s t (Test 2) was con d u c t e d . In Test 2, r a t s t h a t had p r e v i o u s l y s e r v e d i n the motion c o n d i t i o n were t e s t e d i n the r e s t r a i n t c o n d i t i o n , whereas r a t s t h a t had s e r v e d i n the r e s t r a i n t c o n d i t i o n i n Test 1 were t e s t e d i n the motion c o n d i t i o n . Each r a t t h e n , was t e s t e d i n both the motion and r e s t r a i n t c o n d i t i o n s . The e x p e r i m e n t a l d e s i g n was thus a 3 X 2 r e p e a t e d measures d e s i g n , c o u n t e r b a l a n c e d f o r t e s t o r d e r . An a d d i t i o n a l 18 a n i m a l s t h a t had p r e v i o u s l y s e r v e d i n v a r i o u s p i l o t e x p e r i m e n t s , a l s o underwent s u r g e r y i n o r d e r t o det e r m i n e the e f f e c t i v e n e s s of the s u r g i c a l p r o c e d u r e s i n p r o d u c i n g v e s t i b u l a r d y s f u n c t i o n . S i x r a t s s e r v e d i n each of the t h r e e s u r g i c a l c o n d i t i o n s d e s c r i b e d above. F o l l o w i n g the 14-day r e c o v e r y p e r i o d , a l l r a t s were t e s t e d i n a b a t t e r y of t h r e e t e s t s d e s i g n e d t o e v a l u a t e v e s t i b u l a r d y s f u n c t i o n (Modianos & P f a f f , 1976). The f i r s t t e s t was the b a l a n c e beam t e s t f o r v e s t i b u l a r d y s f u n c t i o n t h a t had a l s o been used i n Experiment 3. F o l l o w i n g the beam t e s t , each r a t was p l a c e d on a 64 f l a t t a b l e t o p and r a t e d on two 3 - p o i n t s c a l e s f o r head and body p o s i t i o n d u r i n g a 10 sec o b s e r v a t i o n p e r i o d . Head p o s i t i o n was s c o r e d as 0- i f the head was p r e d o m i n a n t l y h e l d above h o r i z o n t a l , 1- i f the head was h e l d h o r i z o n t a l , and .2- i f the head was u s u a l l y h e l d below h o r i z o n t a l . Body p o s i t i o n was s c o r e d as 0- i f the body was h e l d so t h a t the v e n t r a l s u r f a c e was i n c o n t i n o u s c o n t a c t w i t h the t a b l e t o p , 1- i f the v e n t r a l s u r f a c e was u s u a l l y or p a r t i a l l y e l e v a t e d from the t a b l e t o p , and 2- i f the v e n t r a l s urface.was always e l e v a t e d . Normal r a t s i n our l a b o r a t o r y t y p i c a l l y s c o r e from 2 t o 4 i n the beam t e s t and 1 t o 2 i n the head and body p o s i t i o n t e s t s . RESULTS AND DISCUSSION As shown i n F i g u r e 8, r a t s w i t h d e f e c t i v e v e s t i b u l a r systems do not show the e l e v a t i o n of t a i l w i t h d r a w a l l a t e n c i e s shown by r a t s i n both the o p e r a t e d c o n t r o l and a n e s t h e t i z e d c o n t r o l groups a f t e r exposure t o abnormal m o t i o n . A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of motion (F=22.15, d f = l / 3 0 , p<.05), a s i g n i f i c a n t e f f e c t of s u r g i c a l c o n d i t i o n (F=8.37, df=2/30, p<.05 ) and a s i g n i f i c a n t motion by s u r g e r y i n t e r a c t i o n (F=9.22, df=2/30, p<.05). Post-hoc a n a l y s e s (Tukey) i n d i c a t e d t h a t t a i l w i t h d r a w a l l a t e n c i e s f o r v e s t i b u l a r damaged r a t s d i d not d i f f e r i n the motion and r e s t r a i n t c o n d i t i o n s (p>.05), whereas r a t s i n b o t h the o p e r a t e d and a n e s t h e t i z e d c o n t r o l groups d i s p l a y e d s i g n i f i c a n t l y h i g h e r t a i l w i t h d r a w a l l a t e n c i e s as a r e s u l t of exposure t o abnormal motion (p<.05). The e f f e c t i v e n e s s of the v a r i o u s s u r g i c a l t r e a t m e n t s i n p r o d u c i n g v e s t i b u l a r d y s f u n c t i o n i s i l l u s t r a t e d i n F i g u r e 9. In b o t h the b a l a n c e beam and head p o s i t i o n t e s t , a n i m a l s i n the 65 FIGURE 8. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r the p e r i p h e r a l v e s t i b u l a r a p p a r a t u s l e s i o n (VESTIB LESION), the o p e r a t e d c o n t r o l (OPER CONTROL), and the a n e s t h e t i z e d c o n t r o l (ANES CONTROL) groups of Experiment 6 a f t e r exposure t o motion or r e s t r a i n t . 66 o 1 0 -CD (/) 9 ->-ON 8 -LU 7 -_ l 6 -_J < 5 -< CC Q 4 -X I- 3 -2 -_J TAI 1 -| | RESTRAINT MOTION X I VESTIB OPER ANES LESION CONTROL CONTROL 67 FIGURE 9. R e s u l t s of v e s t i b u l a r d y s f u n c t i o n t e s t s i n Experiment 6. R a t s i n the p e r i p h e r a l v e s t i b u l a r a p p a r a t u s l e s i o n (VESTIB LESION), o p e r a t e d c o n t r o l (OPER CONTROL), and a n e s t h e t i z e d c o n t r o l (ANES CONTROL) groups were t e s t e d i n a b a l a n c e beam t e s t and were a l s o s c o r e d on head p o s i t i o n and body p o s i t i o n measures. BODY POSITION HEAD POSITION ro CO I r o CO I B E A M TEST S C O R E rO CO I I I < r- m m co 0) d oo o o O "o 2 m H 3D O > O Z 2 m H 0) H * ON C O 69 v e s t i b u l a r - d a m a g e d c o n d i t i o n showed s i g n i f i c a n t performance d e f i c i t s when compared t o the a n e s t h e t i z e d and o p e r a t e d c o n t r o l groups (F=23.82, df=2/15, p<.05 and F=4.20, df=2/15, p<.05, r e s p e c t i v e l y ) . In the body p o s i t i o n t e s t , a s i g n i f i c a n t main e f f e c t was found (F=7.31, df=2/15, p<.05) but post-hoc t e s t s (Tukey) r e v e a l e d t h a t the v e s t i b u l a r damaged r a t s d i d not d i f f e r from the a n e s t h e t i z e d c o n t r o l r a t s (p>.05). In no case d i d o p e r a t e d c o n t r o l and a n e s t h e t i z e d c o n t r o l r a t s d i f f e r s i g n i f i c a n t l y . These r e s u l t s t h e n , p r o v i d e s t r o n g s u p p o r t f o r the assumption t h a t the v e s t i b u l a r system i s of p r i m a r y importance i n m e d i a t i n g the a n t i n o c i c e p t i v e e f f e c t of abnormal motion. When the v e s t i b u l a r system was rendered n o n - f u n c t i o n a l by d e s t r u c t i o n of the p e r i p h e r a l r e c e p t o r organs, the a n t i n o c i c e p t i v e e f f e c t of abnormal motion d i d not appear. T h i s f i n d i n g i s c o n s i s t e n t w i t h t h a t . o f a number of o t h e r s t u d i e s t h a t i n d i c a t e a p r i m a r y r o l e f o r the v e s t i b u l a r system i n the b e h a v i o u r a l e f f e c t s of abnormal motion ( G r a y b i e l , 1965; H a r o u t u n i a n , R i c c i o , & Gans, 1976; Money, 1970) but i s the f i r s t e v i d e n c e t h a t the v e s t i b u l a r system i s e s s e n t i a l f o r the a n t i n o c i c e p t i v e e f f e c t of abnormal motion. Experiment 1_ I t i s c l e a r from the r e s u l t s of Experiment 6 t h a t the v e s t i b u l a r system i s n e c e s s a r y f o r the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . The p e r i p h e r a l r e c e p t o r l e s i o n s used i n Experiment 6 d i s r u p t e d a l l r e c e p t o r i n p u t t o the c e n t r a l v e s t i b u l a r n u c l e i , the p r i m a r y p r o c e s s i n g and r e l a y n u c l e i of 70 the v e s t i b u l a r system ( B a l o h & H o n r u b i a , 1979; B r o d a l , Pompeiano, & Walberg, 1962). A l t h o u g h an i n t a c t v e s t i b u l a r r e c e p t o r seemed c r i t i c a l f o r the a n t i n o c i c e p t i v e e f f e c t , the r o l e of the c e n t r a l nervous system v e s t i b u l a r s t r u c t u r e s remained unknown. W i t h i n the b r a i n s t e m t h e r e are f o u r c e n t r a l v e s t i b u l a r n u c l e i t h a t r e c e i v e t o p o g r a p h i c p r o j e c t i o n s from the p e r i p h e r a l l a b y r i n t h i n e and o t o l i t h i c r e c e p t o r mechanisms (Gacek, 1975). In a d d i t i o n , t h e r e a r e d i r e c t and i n d i r e c t p r o j e c t i o n s from the p e r i p h e r a l r e c e p t o r s and n u c l e i t o c e r e b e l l a r n u c l e i (Gacek, 1975). I t i s unknown whether any of the s e c e n t r a l s t r u c t u r e s a r e of p r i m a r y importance i n m e d i a t i n g the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . A c c o r d i n g l y , the p r e s e n t experiment was d e s i g n e d t o e x p l o r e the p o s s i b l e r o l e of some of the s e c e n t r a l v e s t i b u l a r mechanisms i n the m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t . METHOD S u b j e c t s and Surgery S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 40 male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 300 gm a t the time of s u r g e r y . S u b j e c t s were housed, p u r c h a s e d , and m a i n t a i n e d as d e s c r i b e d i n p r e v i o u s e x p e r i m e n t s . Ten r a t s were randomly a s s i g n e d t o each of f o u r l e s i o n g roups. Three of t h e s e groups r e c e i v e d b i l a t e r a l l e s i o n s of the m e d i a l v e s t i b u l a r n u c l e u s (MVN), the l a t e r a l v e s t i b u l a r n u c l e u s (LVN), and c e r e b e l l u m d o r s a l t o the l a t e r a l and m e d i a l v e s t i b u l a r n u c l e u s (CER), whereas, the f o u r t h group a c t e d as a sham l e s i o n c o n t r o l group (SHAM). Of the f o u r v e s t i b u l a r n u c l e i , o n l y the l a t e r a l and m e d i a l v e s t i b u l a r n u c l e i were chosen f o r i n v e s t i g a t i o n because 71 they a r e r e l a t i v e l y l a r g e and a c c e s s i b l e i n the r a t . A l l r a t s were a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l (Nembutal, 50 mg/kg, i . p . ) and mounted i n a s t e r e o t a x i c head-h o l d e r . The s c a l p was i n c i s e d and r e t r a c t e d and two s m a l l h o l e s were d r i l l e d i n the s k u l l d o r s a l t o the l o c a t i o n of the i n t e n d e d l e s i o n . S t e r e o t a x i c l e s i o n c o o r d i n a t e s were m o d i f i e d from those of Modianos and P f a f f (1976) and were as f o l l o w s : MVN, 4.0 mm p o s t e r i o r t o lambda, + 0.8 mm l a t e r a l t o m i d l i n e , 5.6 mm v e n t r a l t o the d u r a ; LVN, -3.8 mm p o s t . , 1.8 mm l a t . , 5.6 mm v e n t r a l ; CER, same p o s t , and l a t . measurements as MVN (n = 5) and LVN (n = 5 ) , 4.0 mm v e n t r a l ; SHAM, same p o s t . and l a t . measurements as MVN (n = 5) and LVN (n = 5 ) , 5.0 mm v e n t r a l . A l l a n t e r i o r - p o s t e r i o r measurements were p o s t e r i o r t o lambda w i t h the s k u l l l e v e l from bregma t o lambda. A s t a i n l e s s s t e e l e l e c t r o d e ( s i z e '00' i n s e c t p i n , i n s u l a t e d w i t h v a r a t h a n e except .5 mm a t the t i p ) was then lowered t o the a p p r o p r i a t e depth and an o d a l d i r e c t c u r r e n t was passed between the e l e c t r o d e and an a n a l c a t h o d e . C u r r e n t parameters were as f o l l o w s : MVN l e s i o n s , .3 mA f o r 15 s e c ; LVN, .4 mA f o r 15 s e c ; CER, .3 mA f o r 15 s e c ; Sham l e s i o n e d r a t s underwent a s i m i l a r p r o c e d u r e except t h a t the e l e c t r o d e was lowered t o a p o i n t j u s t d o r s a l t o the MVN (n = 5) or LVN (n = 5) and no c u r r e n t was passed. One r a t from each of the MVN, LVN, and SHAM l e s i o n groups d i e d f o l l o w i n g s u r g e r y but p r i o r t o b e h a v i o u r a l t e s t i n g . P r o c e d u r e On each of 3 days p r i o r t o t e s t i n g , r a t s were i n d i v i d u a l l y adapted t o the r e s t r a i n i n g tubes f o r a 5 min p e r i o d . On the f i r s t day of t e s t i n g , h a l f of the r a t s i n each l e s i o n group were 72 a s s i g n e d t o the motion c o n d i t i o n , whereas, the r e m a i n i n g r a t s i n each group s e r v e d i n the r e s t r a i n t c o n d i t i o n . R a t s i n the motion c o n d i t i o n were s u b j e c t e d to^ the s w i n g i n g motion used p r e v i o u s l y (30 s w i n g s ) . Immediately f o l l o w i n g the t e r m i n a t i o n of the motion or r e s t r a i n t p e r i o d , the s t a n d a r d h o t - w a t e r t a i l w i t h d r a w a l t e s t f o r a n a l g e s i a was a d m i n i s t e r e d . Immediately f o l l o w i n g the t a i l movement t e s t , the b a l a n c e beam t e s t f o r v e s t i b u l a r d y s f u n c t i o n was a d m i n i s t e r e d . On the second day of t e s t i n g , the same pr o c e d u r e was r e p e a t e d except t h a t the r a t s t h a t had been S u b j e c t e d t o abnormal motion on the f i r s t day of t e s t i n g now s e r v e d i n the r e s t r a i n t c o n d i t i o n and v i c e v e r s a . B a l a n c e beam t e s t s were a g a i n a d m i n i s t e r e d on Day 2. The e x p e r i m e n t a l d e s i g n was thus s i m i l a r t o t h a t of Experiment 6. T a i l f l i c k l a t e n c i e s and b a l a n c e s c o r e s were combined a c r o s s subgroups i n the c e r e b e l l a r and sham l e s i o n groups, thus p r o v i d i n g a 4 X 2 r e p e a t e d measures d e s i g n w i t h the f o u r l e s i o n c o n d i t i o n s and the two a n a l g e s i a t e s t s as the l e v e l s of the two f a c t o r s . F o l l o w i n g b e h a v i o u r a l t e s t i n g , a l l r a t s were k i l l e d i n a carbon d i o x i d e chamber and p e r f u s e d i n t r a - c a r d i a l l y w i t h a .9% s a l i n e s o l u t i o n f o l l o w e d by a 10% F o r m a l i n s o l u t i o n . The b r a i n s were then removed and s e r i a l c o r o n a l f r o z e n s e c t i o n s (30 um) were ta k e n and mounted on s l i d e s t o p e r m i t e x a m i n a t i o n of l e s i o n s i z e and l o c a t i o n . RESULTS AND DISCUSSION H i s t o l o g i c a l r e s u l t s F i g u r e 10 i l l u s t r a t e s the r e s u l t s of h i s t o l o g i c a l a n a l y s i s and d e p i c t s b o t h maximal and t y p i c a l l e s i o n s i n the LVN, MVN, 73 FIGURE 10. Schematic r e p r e s e n t a t i o n of l e s i o n s i z e and l o c a t i o n i n the m e d i a l v e s t i b u l a r (MVN), l a t e r a l v e s t i b u l a r (LVN), and c e r e b e l l a r (CER) l e s i o n groups of Experiment 10. Shaded a r e a s i n d i c a t e maximal composite e x t e n t of l e s i o n damage w h i l e b l a c k a r e a s i n d i c a t e a t y p i c a l l e s i o n . S e c t i o n s were t a k e n from P e l l e g r i n o and Cushman (1967) and the numbers r e f e r t o the p o s t e r i o r d i s t a n c e of the s e c t i o n from bregma ( i n mm). 74 75 and CER l e s i o n groups. A l l a n i m a l s showed at l e a s t some damage to the i n t e n d e d s t r u c t u r e s but o v e r a l l , the l e s i o n s were not b i l a t e r a l l y c o n s i s t e n t . LVN l e s i o n s tended t o i n c l u d e p o r t i o n s of the MVN and o t h e r a d j a c e n t s t r u c t u r e s such as the s u p e r i o r c e r e b e l l a r p e d u n c l e and s p i n a l t r a c t of the t r i g e m i n a l n e r v e . MVN l e s i o n s , a l t h o u g h i n c o n s i s t e n t , were g e n e r a l l y r e s t r i c t e d t o the MVN w i t h l i t t l e damage t o a d j a c e n t s t r u c t u r e s . CER l e s i o n s u s u a l l y i n c l u d e d damage t o the n u c l e u s i n t e r p o s i t u s and c e r e b e l l a r c o r t e x . L i t t l e or no g r o s s damage was apparent i n the sham l e s i o n e d c o n t r o l group (not shown i n F i g u r e 1 0 ) . A n a l g e s i a t e s t s Mean t a i l w i t h d r a w a l l a t e n c i e s f o r a l l l e s i o n and c o n t r o l groups a r e shown i n F i g u r e 11. A n a l y s i s of v a r i a n c e i n d i c a t e d o n l y a s i g n i f i c a n t a n t i n o c i c e p t i v e e f f e c t of abnormal motion v e r s u s r e s t r a i n t (F=24.13, d f = l / 3 3 , p<.05). A l t h o u g h the mean a n t i n o c i c e p t i v e measures shown i n F i g u r e 11 a r e perhaps s u g g e s t i v e of a b l o c k i n g e f f e c t of the LVN and CER l e s i o n s , the a n a l y s i s of v a r i a n c e i n d i c a t e d no s i g n i f i c a n t d i f f e r e n c e s among l e s i o n c o n d i t i o n s (F=.39, df=3/33, p>.05) and no s i g n i f i c a n t i n t e r a c t i o n between l e s i o n t y pe and motion or r e s t r a i n t (F=1.18, df=3/33, p>.05). B a l a n c e t e s t s As shown i n F i g u r e 12, o n l y LVN l e s i o n s r e s u l t e d i n p r o f o u n d v e s t i b u l a r d y s f u n c t i o n as measured by the b a l a n c e beam t e s t . A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t (F=22.93, df=3/33, p<.05) e f f e c t of type of l e s i o n , but t h e r e was no s i g n i f i c a n t e f f e c t of exposure t o abnormal motion on subsequent 76 FIGURE 11. R e s u l t s of Experiment 7, d e p i c t i n g the e f f e c t s of abnormal motion on t a i l w i t h d r a w a l l a t e n c i e s i n the m e d i a l v e s t i b u l a r (MVN), l a t e r a l v e s t i b u l a r (LVN), c e r e b e l l a r (CER), and sham (SHAM) l e s i o n groups. u CD C/) o z UJ < cc Q X 9 8 7 6 5 4 3 2 1 I H MOTION • RESTRAINT I I X MVN LVN CER SHAM 78 FIGURE 12. E f f e c t s of motion and r e s t r a i n t on b a l a n c e beam s c o r e s i n the m e d i a l v e s t i b u l a r (MVN), l a t e r a l v e s t i b u l a r (LVN), c e r e b e l l a r (CER), and sham (SHAM) l e s i o n groups of Experiment 7. < 2-LU CD | | MOTION j RESTRAINT i T , T MVN LVN CER i i SHAM 80 a b i l i t y t o p e r f o r m i n the b a l a n c e beam task (F=.45, d f = l / 3 3 , p>.05). In a d d i t i o n , t h e r e was no s i g n i f i c a n t i n t e r a c t i o n between type of l e s i o n and motion c o n d i t i o n (F=.32, df=3/33, p>.05). Perhaps the most i m p o r t a n t c o n c l u s i o n t o be reached from t h e s e d a t a c o n c e r n s the f a c t t h a t performance on the b a l a n c e beam does not appear t o be d i s r u p t e d by exposure t o abnormal moti o n . N e i t h e r the MVN or SHAM l e s i o n l e s i o n g roups, both of which demonstrated a c l e a r a n t i n o c i c e p t i v e response i n the t a i l w i t h d r a w a l t e s t , appeared t o s u f f e r any performance d e f i c i t i n the subsequent beam t e s t . T h i s would suggest t h a t ' d i z z i n e s s ' i s not a f a c t o r i n the a n t i n o c i c e p t i v e e f f e c t produced by the s w i n g i n g m o t i o n . The b a l a n c e beam t e s t , a l t h o u g h subsequent t o the a n a l g e s i a t e s t , was a d m i n i s t e r e d w e l l w i t h i n the d u r a t i o n of the a n t i n o c i c e p t i v e response e s t a b l i s h e d i n Experiment 1 w i t h an i d e n t i c a l motion s t i m u l u s . The f a i l u r e of MVN l e s i o n s t o produce a d e f i c i t i n the b a l a n c e beam t e s t i s somewhat p u z z l i n g . Soon a f t e r s u r g e r y , t h e s e r a t s were e x h i b i t i n g symptoms s i m i l a r b o t h t o those produced by LVN l e s i o n s i n the p r e s e n t experiment and the p e r i p h e r a l v e s t i b u l a r a p p a r a t u s l e s i o n s of Experiment 6. By the time of t e s t i n g however, t h e s e MVN l e s i o n e d r a t s were a b l e t o p e r f o r m i n the b a l a n c e beam t e s t as w e l l as the sham and c e r e b e l l a r l e s i o n e d r a t s , none of whom showed any s i g n of v e s t i b u l a r d y s f u n c t i o n f o l l o w i n g s u r g e r y . I t seems t h e n , t h a t t h e r e i s a r a p i d r e c o v e r y of f u n c t i o n f o l l o w i n g MVN l e s i o n s . T h i s r a p i d r e c o v e r y of f u n c t i o n f o l l o w i n g MVN l e s i o n s has a l s o been noted by Modianos and P f a f f (1976) i n a stu d y of v e s t i b u l a r 81 i n t e r a c t i o n s i n female r a t s e x u a l b e h a v i o u r . In t h i s s t u d y , MVN l e s i o n s were found t o produce s e v e r e d y s f u n c t i o n soon a f t e r s u r g e r y but t h i s d y s f u n c t i o n was f o l l o w e d by a r a p i d r e c o v e r y t o near normal l e v e l s of performance w i t h i n 2 weeks. G i v e n the 2 week d e l a y between s u r g e r y and t e s t i n g used i n the p r e s e n t e x p e r i m e n t , t h i s r a p i d r e c o v e r y may w e l l e x p l a i n the a p p a r e n t l y normal performance of the MVN l e s i o n e d a n i m a l s i n the b a l a n c e t a s k . A n i m a l s w i t h LVN l e s i o n s i n the Modianos and P f a f f (1976) study demonstrated v e s t i b u l a r d y s f u n c t i o n f o r much l o n g e r p e r i o d s of time w i t h a much slowe r r e c o v e r y of f u n c t i o n , a l s o c o n s i s t e n t w i t h the r e s u l t s of the p r e s e n t e x p e r i m e n t . From t h e s e d a t a , i t i s i m p o s s i b l e t o d e l i n e a t e a r e l a t i o n s h i p between the a n t i n o c i c e p t i v e e f f e c t of abnormal motion and c e r t a i n c e n t r a l n e u r a l s t r u c t u r e s t h a t a r e presumably r e s p o n s i b l e f o r i n t e g r a t i n g and p r o c e s s i n g i n f o r m a t i o n c o n c e r n i n g the p r o v o c a t i v e s t i m u l u s . I t remains p o s s i b l e t h a t such a r e l a t i o n s h i p e x i s t s and the f a i l u r e t o uncover the r e l a t i o n s h i p s here i s merely a f u n c t i o n of the t e c h n i q u e s used i n the i n v e s t i g a t i o n or the l i m i t e d number of s t r u c t u r e s i n v e s t i g a t e d . L e s i o n t e c h n i q u e s s u f f e r from a v a r i e t y of d i f f i c u l t i e s i n c l u d i n g i o n d e p o s i t i o n , i n c o n s i s t e n t l e s i o n s i z e and l o c a t i o n , g l i a l f o r m a t i o n around the l e s i o n s i t e , e t c . (see I s a a c s o n , 1976), and hence may not be s u f f i c i e n t l y r e f i n e d or s e n s i t i v e . The f o l l o w i n g experiment attempted t o e x p l o r e t h i s p o s s i b l e b r a i n - b e h a v i o u r r e l a t i o n s h i p u s i n g a d i f f e r e n t t e c h n i q u e , e l e c t r i c a l b r a i n s t i m u l a t i o n . 82 Experiment 8 Experiment 8 attempted t o a g a i n i n v e s t i g a t e the p o s s i b l e involvement of some components of the c e n t r a l v e s t i b u l a r system i n the n e u r a l m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal v e s t i b u l a r s t i m u l a t i o n . I f any of the s e components of the c e n t r a l v e s t i b u l a r system a r e i n v o l v e d i n the d i r e c t m e d i a t i o n of a n t i n o c i c e p t i o n , the d i r e c t e l e c t r i c a l s t i m u l a t i o n of t h e s e components might e l i c i t an a n t i n o c i c e p t i v e e f f e c t . In the p r e s e n t e x p e r i m e n t , e l e c t r o d e s were i m p l a n t e d i n the l a t e r a l v e s t i b u l a r n u c l e u s (LVN), m e d i a l v e s t i b u l a r n u c l e u s , and c e r e b e l l u m . A n t i n o c i c e p t i o n was a s s e s s e d u s i n g the t a i l w i t h d r a w a l t e s t f o l l o w i n g a p e r i o d of e l e c t r i c a l s t i m u l a t i o n . METHOD S u b j e c t s and Sur g e r y S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 30 male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 350 gms a t the time of s u r g e r y . F o l l o w i n g s u r g e r y , a l l r a t s were i n d i v i d u a l l y housed i n s t a n d a r d hanging w i r e mesh cage s , under a r e v e r s e d 12 hr l i g h t / d a r k c y c l e . Food and water were f r e e l y a v a i l a b l e a t a l l t i m e s . A l l r a t s were a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l (Nembutal, 50 mg/kg, i . p . ) and mounted i n a s t e r e o t a x i c h e a d h o l d e r . S m a l l s t a i n l e s s s t e e l screws were s e c u r e d i n h o l e s d r i l l e d i n the s k u l l t o p r o v i d e an anchor f o r the a c r y l i c cement ( F l a s h D e n t a l A c r y l i c ) used t o a f f i x t he e l e c t r o d e . Once b u r r h o l e s had been p l a c e d i n the s k u l l i n the a p p r o p r i a t e l o c a t i o n s , a u n i l a t e r a l b i p o l a r e l e c t r o d e was lowered t o the a p p r o p r i a t e l o c a t i o n w i t h i n the b r a i n . E l e c t r o d e s were c o n s t r u c t e d of .6 mm 83 di a m e t e r i n s u l a t e d nichrome w i r e t w i s t e d t o g e t h e r t o form a s p i r a l - w o u n d p a i r of w i r e s . The e l e c t r o d e t i p s were s c r a p e d c l e a n of i n s u l a t i o n f o r a p p r o x i m a t e l y .2 mm at the t i p s and the t i p s s e p a r a t e d by a p p r o x i m a t e l y .5 mm. These b i p o l a r e l e c t r o d e s were i m p l a n t e d i n t h r e e l o c a t i o n s w i t h i n the c e n t r a l v e s t i b u l a r system: the l a t e r a l v e s t i b u l a r n u c l e u s , the m e d i a l v e s t i b u l a r n u c l e u s , or the c e r e b e l l u m d o r s a l t o the l a t e r a l and m e d i a l v e s t i b u l a r n u c l e u s . A l l c o o r d i n a t e s were based on a l e v e l s k u l l and were i d e n t i c a l t o th o s e d e s c r i b e d i n Experiment 7. Once the e l e c t r o d e was i n p l a c e , a c r y l i c cement was used t o sec u r e the e l e c t r o d e and t o b u i l d up a smooth cap on the s k u l l c o n t a i n i n g the t e r m i n a l c o n n e c t o r s f o r the e l e c t r o d e . A 30 day r e c o v e r y p e r i o d was a l l o w e d t o e l a p s e between s u r g e r y and b e h a v i o u r a l t e s t i n g . P r o c e d u r e A n a l g e s i a t e s t i n g was co n d u c t e d over two c o n s e c u t i v e days. Each r a t r e c e i v e d b r a i n s t i m u l a t i o n f o l l o w e d by the hot-water t a i l w i t h d r a w a l t e s t one day and on the o t h e r , an e q u i v a l e n t p e r i o d of no s t i m u l a t i o n was f o l l o w e d by the t a i l w i t h d r a w a l t e s t . Each of the t h r e e i m p l a n t groups (LVN, MVN, and CER) was d i v i d e d i n two; h a l f of the group r e c e i v e d b r a i n s t i m u l a t i o n the f i r s t day and a n o - s t i m u l a t i o n t e s t on the second, whereas the remainder of the group r e c e i v e d a n o - s t i m u l a t i o n t e s t the f i r s t day and b r a i n s t i m u l a t i o n t h e second day. The d e s i g n was thus a 3 X 2 r e p e a t e d measure d e s i g n , c o u n t e r b a l a n c e d f o r t e s t o r d e r . In the s t i m u l a t i o n c o n d i t i o n , r a t s were c o n n e c t e d by l i g h t w e i g h t l e a d s t o a 60 Hz sine-wave s t i m u l a t o r . S t i m u l a t i o n parameters were c o n t r o l l e d by a s o l i d - s t a t e t i m i n g d e v i c e t h a t 84 produced a s t i m u l a t i o n p a t t e r n of 10 sec on f o l l o w e d by 10 sec o f f . T h i s c y c l e was r e p e a t e d f o r the d u r a t i o n of the 5 min s t i m u l a t i o n p e r i o d . C u r r e n t i n t e n s i t y was a d j u s t e d f o r each r a t i m m e d i a t e l y p r e c e d i n g the 5 min s t i m u l a t i o n p e r i o d so t h a t the s t i m u l a t i o n produced a n o t i c e a b l e b e h a v i o u r a l e f f e c t . S t i m u l a t i o n i n t e n s i t y was l i m i t e d t o a maximum of 150 ua t o p r e v e n t p o s s i b l e damage a t the e l e c t r o d e t i p . The b e h a v i o u r a l e f f e c t s o b s e r v e d t y p i c a l l y c o n s i s t e d of head t u r n i n g and a d r a m a t i c l o s s of b a l a n c e . Immediately f o l l o w i n g the l a s t 10 sec s t i m u l a t i o n p e r i o d , the r a t was p l a c e d i n a r e s t r a i n i n g tube and the h o t - w a t e r t a i l w i t h d r a w a l t e s t f o r a n t i n o c i c e p t i o n was co n d u c t e d . Rats i n the n o - s t i m u l a t i o n c o n d i t i o n were connected t o the s t i m u l a t o r l e a d s but no b r a i n s t i m u l a t i o n was d e l i v e r e d . F o l l o w i n g b e h a v i o u r a l t e s t i n g , the r a t s were k i l l e d i n a carbon d i o x i d e chamber and p e r f u s e d i n t r a - c a r d i a l l y w i t h a .9% s a l i n e s o l u t i o n f o l l o w e d by a 10% F o r m a l i n s o l u t i o n . The b r a i n s were removed and s e r i a l f r o z e n c o r o n a l s e c t i o n s were t a k e n a t a t h i c k n e s s of 30 um. B r a i n s e c t i o n s were mounted on s l i d e s and p r o j e c t e d t h r o u g h a p r o j e c t i o n m i c r o s c o p e t o p e r m i t e x a m i n a t i o n of e l e c t r o d e l o c a t i o n s . RESULTS H i s t o l o g i c a l r e s u l t s Two a n i m a l s were l o s t from t h e LVN i m p l a n t group f o l l o w i n g s u r g e r y and p r i o r t o t e s t i n g due t o a f a i l u r e of the e l e c t r o d e cap assembly. E l e c t r o d e placements f o r the r e m a i n i n g a n i m a l s a r e shown i n F i g u r e 13. Three a n i m a l s i n the MVN group had e l e c t r o d e s o u t s i d e the MVN and hence were d e l e t e d from the a n a l y s i s . S i m i l a r l y , two a n i m a l s were d e l e t e d from the LVN 85 FIGURE 13. L o c a t i o n s of s t i m u l a t i n g e l e c t r o d e s i n the m e d i a l v e s t i b u l a r (MVN), l a t e r a l v e s t i b u l a r (LVN), and c o n t r o l i m p l a n t groups of Experiment 8. 86 87 group and one from the c e r e b e l l a r i m p l a n t group. A n a l g e s i a t e s t s As shown i n F i g u r e 14, e l e c t r i c a l s t i m u l a t i o n of the LVN, MVN, or c e r e b e l l u m d i d not produce any o b v i o u s changes i n t a i l w i t h d r a w a l l a t e n c i e s . A n a l y s i s of v a r i a n c e i n d i c a t e d no s i g n i f i c a n t e f f e c t of e l e c t r i c a l s t i m u l a t i o n w i t h any e l e c t r o d e placement (F=.46, df=2/19, p>.05; F=.33, d f = l / 1 9 , p>.05). I t was c l e a r from i n f o r m a l o b s e r v a t i o n t h a t a l l s u b j e c t s i n c l u d e d i n the a n a l y s i s e x h i b i t e d b e h a v i o u r s c o n s i s t e n t w i t h s t i m u l a t i o n of the v e s t i b u l a r system (Modianos & P f a f f , 1977). The most f r e q u e n t r e s u l t of s t i m u l a t i o n was a t i l t i n g of the body and the head i n the MVN and LVN p l a c e m e n t s . C e r e b e l l a r placements produced a v a r i e t y of e f f e c t s t h a t were l e s s c o n s i s t e n t than the LVN and MVN b e h a v i o u r s such as t i l t i n g t o the r i g h t or l e f t , f a l l i n g f o r w a r d , or no e f f e c t . E l e c t r o d e placements o u t s i d e the i n t e n d e d s t i m u l a t i o n s i t e s g e n e r a l l y produced e i t h e r no e f f e c t or b e h a v i o u r a l e f f e c t s q u a l i t a t i v e l y d i f f e r e n t than those produced by LVN or MVN s t i m u l a t i o n . These s t i m u l u s bound e f f e c t s i n c l u d e d chewing and l i c k i n g d i r e c t e d a t t h e f l o o r of the cage or body appendages, in vacuo chewing and f a c i a l movements, and i n one c a s e , backwards w a l k i n g and r a p i d r e s p i r a t i o n . S t i m u l a t i o n i n t h e s e s i t e s a l s o d i d not produce a n o t i c e a b l e a n t i n o c i c e p t i v e e f f e c t i n t h e p r e s e n t e x p e r i m e n t . The r e s u l t s of the p r e s e n t e x p e r i m e n t u s i n g e l e c t r i c a l s t i m u l a t i o n f a i l e d t o f i n d a c l e a r r e l a t i o n s h i p between c e n t r a l v e s t i b u l a r components and the a n t i n o c i c e p t i v e e f f e c t of abnormal motion. These d a t a , c o n s i d e r e d w i t h the r e s u l t s of Experiment 7, which i n v o l v e d the l e s i o n t e c h n i q u e , would suggest t h a t i f 88 FIGURE 14. E f f e c t s of e l e c t r i c a l s t i m u l a t i o n i n the m e d i a l v e s t i b u l a r n u c l e u s (MVN), l a t e r a l v e s t i b u l a r n u c l e u s (LVN), or c e r e b e l l u m (CER) on t a i l w i t h d r a w a l l a t e n c i e s i n Experiment 8. 89 S >-o z LU _ J I DC Q X h-8 5 2 < 1 i HI STIMULATED • CONTROL I I X 1 MVN LVN CER 90 t h i s r e l a t i o n s h i p e x i s t s , i t i s not a s i m p l e one. I t would seem, t h a t the a n t i n o c i c e p t i v e response i s not o b v i o u s l y mediated by any one component of the c e n t r a l v e s t i b u l a r system. I t i s p o s s i b l e t h e n , t h a t the a n t i n o c i c e p t i v e e f f e c t i s mediated by the i n t e r a c t i o n of the v a r i o u s components and s e l e c t i v e l y e l i m i n a t i n g or a c t i v a t i n g one component cannot r e v e a l the n a t u r e of the i n t e r a c t i o n . I t i s a l s o p o s s i b l e t h a t o t h e r f a c t o r s i n the p r e s e n t experiment c o u l d have ob s c u r e d the p r e s e n c e of an e x i s t i n g one-to-one c o r r e s p o n d e n c e between a n t i n o c i c e p t i o n and a p a r t i c u l a r v e s t i b u l a r component. F i r s t , the s m a l l group s i z e s t h a t remained f o r s t a t i s t i c a l a n a l y s i s f o l l o w i n g h i s t o l o g i c a l a n a l y s i s may have d e c r e a s e d the power of the a n a l y s i s s u f f i c i e n t l y t h a t an a n t i n o c i c e p t i v e e f f e c t was not d e t e c t e d . Second, the n o n - p h y s i o l o g i c a l n a t u r e of the e l e c t r i c a l s t i m u l a t i o n i t s e l f may a l s o have masked the i n v o l v e m e n t of p a r t i c u l a r components. That i s , i t i s u n l i k e l y t h a t the- p a t t e r n and i n t e n s i t y of e l e c t r i c a l s t i m u l a t i o n used here a c t i v a t e s v e s t i b u l a r components i n a manner t h a t e x a c t l y resembles a c t i v a t i o n produced by the normal i n n e r v a t i o n of t h e s e components. A t h i r d p o s s i b l e c r i t i c i s m a p p l i e s t o the l i m i t e d number of s t i m u l a t i o n s i t e s chosen f o r i n v e s t i g a t i o n . W h i l e the LVN, MVN, and c e r e b e l l u m a r e the l a r g e s t and perhaps major components of the r a t v e s t i b u l a r system, t h e r e a r e o t h e r components such as the d e s c e n d i n g and s u p e r i o r v e s t i b u l a r n u c l e i (Gacek, 1 9 7 5 ) t h a t were not i n v e s t i g a t e d h e r e . The p o s s i b i l i t y t h a t d i z z i n e s s r e s u l t i n g from v e s t i b u l a r 91 s t i m u l a t i o n i s the p r i m a r y e x p l a n a t i o n f o r the a n t i n o c i c e p t i v e e f f e c t i s a l s o a d d r e s s e d h e r e . The e l e c t r i c a l s t i m u l a t i o n used i n the p r e s e n t study produced b e h a v i o u r a l e f f e c t s ( l o s s of b a l a n c e , head t i l t , e t c . ) c o n s i s t e n t w i t h d i z z i n e s s . T h i s s t i m u l a t i o n - i n d u c e d ' d i z z i n e s s ' however, produced no d e t e c t a b l e a n a l g e s i c a c t i o n i n the t a i l - w i t h d r a w a l t e s t . I t would seem t h a t a l t h o u g h d i z z i n e s s may c e r t a i n l y r e s u l t from abnormal v e s t i b u l a r f u n c t i o n , i t s r o l e as a c a u s a l f a c t o r i n the a n t i n o c i c e p t i o n phenomenon i s f a r from a s i m p l e r e l a t i o n s h i p . 92 G e n e r a l D i s c u s s i o n ^ S e c t i o n I I The e x p e r i m e n t s c o n t a i n e d i n t h i s s e c t i o n a t t e m p t e d t o e x p l o r e the r o l e of the v e s t i b u l a r system i n an a n t i n o c i c e p t i v e e f f e c t of abnormal motion. The r e s u l t s of Experiment 6 i n d i c a t e t h a t the v e s t i b u l a r system i s indeed an i m p o r t a n t and n e c e s s a r y component f o r the g e n e s i s of the a n t i n o c i c e p t i v e phenomenon. When i n p u t from the v e s t i b u l a r r e c e p t o r organs was removed by d e s t r u c t i o n of the p e r i p h e r a l mechanisms, the a n t i n o c i c e p t i v e e f f e c t of abnormal motion f a i l e d t o o c c u r . I t i s c l e a r t h a t the v e s t i b u l a r system i s an i n t e g r a l p a r t of the a n t i n o c i c e p t i v e response mechanism y e t f u r t h e r a t t e m p t s t o d e l i n e a t e the r e l a t i v e c o n t r i b u t i o n s of some c e n t r a l nervous system components t o t h i s e f f e c t were u n s u c c e s s f u l . A l t h o u g h i t seems r e a s o n a b l e t o suggest t h a t the v e s t i b u l a r system must be i n v o l v e d i n m e d i a t i n g t h i s e f f e c t a t a somewhat h i g h e r l e v e l than the r e c e p t o r l e v e l , no c l e a r - c u t r e l a t i o n s h i p s were found t o e x i s t between the c e n t r a l v e s t i b u l a r s t r u c t u r e s i n v e s t i g a t e d and the a n t i n o c i c e p t i v e e f f e c t . T h i s l a c k of an o b v i o u s r e l a t i o n s h i p between the a n t i n o c i c e p t i v e e f f e c t of v e s t i b u l a r s t i m u l a t i o n and c e n t r a l components of the v e s t i b u l a r system c o u l d be the r e s u l t of a number of f a c t o r s . F i r s t , i t i s p o s s i b l e t h a t the l e s i o n and e l e c t r i c a l s t i m u l a t i o n t e c h n i q u e s used here a r e not s u f f i c i e n t l y r e f i n e d or s e n s i t i v e t o a l l o w d e l i n e a t i o n of the invo l v e m e n t of the v a r i o u s components examined. The e l e c t r o l y t i c l e s i o n t e c h n i q u e s u f f e r s from a v a r i e t y of problems i n c l u d i n g d i f f i c u l t y i n c o n t r o l l i n g the s i z e and l o c a t i o n of the l e s i o n produced, i o n d e p o s i t i o n , e t c . ( I s a a c s o n , 1976), and the e l e c t r i c a l s t i m u l a t i o n t e c h n i q u e 93 used here d i d not e x a c t l y mimic p h y s i o l o g i c a l a c t i v i t y i n the s t r u c t u r e s s t i m u l a t e d . Second, the f a i l u r e t o f i n d an o b v i o u s r e l a t i o n s h i p between the a n t i n o c i c e p t i v e e f f e c t and a p a r t i c u l a r s t r u c t u r e c o u l d i m p l y t h a t no one s p e c i f i c s t r u c t u r e i s d i r e c t l y r e s p o n s i b l e f o r the a n t i n o c i c e p t i v e phenomenon. That i s , the c e n t r a l v e s t i b u l a r system may not be i n v o l v e d t h r o u g h a s p e c i f i c mechanism l i m i t e d t o a p a r t i c u l a r p o r t i o n of the v e s t i b u l a r system but t h r o u g h a much more g e n e r a l mechanism i n v o l v i n g more components. I t i s a l s o p o s s i b l e t h a t the c o m p l e x i t y and f l e x i b i l i t y of the c e n t r a l v e s t i b u l a r system i t s e l f r e n d e r s a s t r a i g h t f o r w a r d l e s i o n or s t i m u l a t i o n approach t o the study of the i n v o l v e m e n t of v a r i o u s components e x t r e m e l y d i f f i c u l t . The r a p i d r e c o v e r y of f u n c t i o n found f o l l o w i n g MVN l e s i o n s i s a case i n p o i n t . I f the MVN were i n v o l v e d i n the a n t i n o c i c e p t i v e e f f e c t , the r a p i d compensation f o r i t s d e s t r u c t i o n by o t h e r mechanisms c o u l d w e l l obscure t h i s r e l a t i o n s h i p . The e x p e r i m e n t s d e s c r i b e d here a l s o p r o v i d e a g r e a t d e a l of u s e f u l i n f o r m a t i o n c o n c e r n i n g the n a t u r e of the a n t i n o c i c e p t i v e r esponse i t s e l f . I t c o u l d perhaps be argued t h a t the apparent a n t i n o c i c e p t i v e e f f e c t of abnormal motion r e f l e c t s n o t h i n g more than a d i r e c t i n h i b i t o r y e f f e c t on the s p i n a l t a i l w i t h d r a w a l r e f l e x used here as a b e h a v i o u r a l measure of a n t i n o c i c e p t i o n . There a r e a number of v e s t i b u l o - s p i n a l p r o j e c t i o n s and t h e s e p r o j e c t i o n s may w e l l a f f e c t s p i n a l r e f l e x b e h a v i o u r s (Gacek, 1975). Modianos and P f a f f (1976a, 1976b) f o r example, have shown t h a t l e s i o n s of b r a i n s t e m and c e r e b e l l a r v e s t i b u l a r n u c l e i r e s u l t i n an i n h i b i t i o n of the s p i n a l l o r d o s i s r e f l e x i n female 94 r a t s and t h a t s t i m u l a t i o n of the s e same s t r u c t u r e s r e s u l t s i n f a c i l i t a t i o n of t h i s same r e f l e x . In c o n t r a s t , the p r e s e n t s e r i e s of e x p e r i m e n t s found t h a t l e s i o n s and e l e c t r i c a l s t i m u l a t i o n of the same s t r u c t u r e s had no e f f e c t on performance of the t a i l w i t h d r a w a l r e f l e x when compared t o n o n - l e s i o n e d c o n t r o l a n i m a l s ( E x p e r i m e n t s 7 and 8 ) . I t s h o u l d a l s o be noted t h a t i f v e s t i b u l a r s t i m u l a t i o n were d i r e c t l y r e l a t e d t o t a i l w i t h d r a w a l performance i n the same manner as t h a t d e s c r i b e d f o r the l o r d o s i s r e f l e x (Modianos & P f a f f , 1977), one would p r e d i c t v e s t i b u l a r s t i m u l a t i o n t o . f a c i l i t a t e r a t h e r than i n h i b i t performance of the t a i l w i t h d r a w a l r e f l e x as seen h e r e . The a n t i n o c i c e p t i v e e f f e c t of abnormal motion t h e n , most p r o b a b l y does not i n v o l v e a d i r e c t v e s t i b u l o - s p i n a l i n h i b i t o r y e f f e c t . The i s s u e of d i z z i n e s s as a r e s u l t of v e s t i b u l a r s t i m u l a t i o n , d i s c u s s e d e a r l i e r as a p o s s i b l e c a u s a l f a c t o r i n the a n t i n o c i c e p t i v e e f f e c t , i s a l s o a d d r e s s e d by the ex p e r i m e n t s p r e s e n t e d i n t h i s s e c t i o n . The e x p e r i m e n t s p r e s e n t e d here p r o v i d e a t l e a s t t h r e e arguements a g a i n s t the ' d i z z i n e s s ' h y p o t h e s i s . F i r s t , l e s i o n s t h a t produce d e f i c i t s i n the b a l a n c e beam t a s k do not n e c e s s a r i l y b l o c k the appearance of an a n t i n o c i c e p t i v e e f f e c t of motion nor do they appear t o produce any a n a l g e s i c e f f e c t t h e m s e l v e s . I f d i z z i n e s s produced a n t i n o c i c e p t i o n i n some s i m p l e f a s h i o n , one would expect a n i m a l s t h a t were d i z z y t o show a l t e r e d b a s e l i n e t a i l w i t h d r a w a l measures r e l a t i v e t o n o n - d i z z y c o n t r o l s . Second, motion t r e a t m e n t s such as s w i n g i n g , a r e c a p a b l e of ' p r o d u c i n g a s i g n i f i c a n t a n t i n o c i c e p t i v e e f f e c t w h i l e not p r o d u c i n g any o t h e r 95 b e h a v i o u r a l e v i d e n c e of v e s t i b u l a r d y s f u n c t i o n . The s w i n g i n g motion used i n Experiment 7 f o r example, produced an a n a l g e s i c e f f e c t w h i l e not a f f e c t i n g performance on a subsequent b a l a n c e beam t e s t . T h i r d , Experiment 8 demonstrated t h a t i t i s p o s s i b l e t o produce b e h a v i o u r a l e v i d e n c e of v e s t i b u l a r d y s f u n c t i o n ( i . e . i n a b i l i t y t o remain u p r i g h t ) t h a t may be analogous t o d i z z i n e s s w i t h o u t p r o d u c i n g an a n t i n o c i c e p t i v e r e s p o n s e . The f o r e g o i n g e x p e r i m e n t s , a l t h o u g h not c o n c l u s i v e , suggest t h a t ' d i z z i n e s s ' i s c e r t a i n l y not r e l a t e d i n any s i m p l e f a s h i o n t o the a n t i n o c i c e p t i v e e f f e c t of abnormal motion. I t i s , of c o u r s e , p o s s i b l e t h a t a r e l a t i o n s h i p does e x i s t but i t seems t h a t t h i s r e l a t i o n s h i p i s not e a s i l y d e l i n e a t e d . In summary t h e n , the e x p e r i m e n t s p r e s e n t e d here demonstrate t h a t the v e s t i b u l a r system i s a n e c e s s a r y component of the p h y s i o l o g i c a l mechanism of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . The f o l l o w i n g s e r i e s of e x p e r i m e n t s a t t e m p t e d t o i n v e s t i g a t e the p h y s i o l o g i c a l mechanisms by which abnormal v e s t i b u l a r s t i m u l a t i o n may e x e r t an e f f e c t on n o c i c e p t i o n . 96 SECTION I I I - Mechanisms of M o t i o n - I n d u c e d A n a l g e s i a The purpose of the e x p e r i m e n t s i n S e c t i o n I I I was t o d e t e r m i n e whether the p h y s i o l o g i c a l mechanisms i n v o l v e d i n m e d i a t i n g the a n t i n o c i c e p t i v e e f f e c t of abnormal motion a r e the same as those t h a t have r e c e n t l y been proposed t o account f o r o t h e r forms of n o n p h a r m a c o l o g i c a l p a i n m o d u l a t i o n . A l t h o u g h a v a r i e t y of n o n p h a r m a c o l o g i c a l t r e a t m e n t s have been r e p o r t e d ( e . g . , M e l z a c k , 1973) t o induce a n a l g e s i a ( e . g . , a c u p u n c t u r e , t r a n s - c u t a n e o u s e l e c t r i c shock, massage, i n t e n s e broad spectrum n o i s e , e l e c t r i c a l b r a i n s t i m u l a t i o n , and h y p n o s i s ) , the p h y s i o l o g i c a l mechanisms u n d e r l y i n g t h e s e e f f e c t s has. been d i f f i c u l t t o a s s e s s . However, two r e c e n t f i n d i n g s have s t i m u l a t e d i n t e r e s t i n t h i s problem. The f i r s t was the d i s c o v e r y of endogenous o p i a t e - l i k e p e p t i d e s w i t h i n the c e n t r a l nervous system, and the second was the d i s c o v e r y of the s t r e s s -i n d u c e d a n a l g e s i a phenomenon. The s t r e s s - i n d u c e d a n a l g e s i a phenomenon i n v o l v e s the presence of a n a l g e s i a f o l l o w i n g exposure of the s u b j e c t t o s e v e r e p h y s i o l o g i c a l s t r e s s o r s such as f o o t s h o c k ( B u c k e t t , 1979; Chesher & Chan, 1977; Hayes, Bennet, Newlon, & Mayer, 1978), immersion i n c o l d water (Bodnar, K e l l y , S p i a g g i a , & Glusman, 1978) , 2-deoxy-D-glucose i n j e c t i o n s (Bodnar, K e l l y , & Glusman, 1979) , i n s u l i n i n j e c t i o n s (Bodnar, K e l l y , Mansour, & Glusman, 1979), exposure t o h i g h g r a v i t y environments (Hayes, Bennet, Newlon, & Mayer, 1978), or food d e p r i v a t i o n (McGivern, B e r k a , B e r n t s o n , Walker, & Sandman, 1979). Exposure t o such p h y s i o l o g i c a l s t r e s s o r s produces a l a r g e a n t i n o c i c e p t i v e e f f e c t i n a v a r i e t y of t e s t s f o r a n a l g e s i a such as r a d i a n t - h e a t t a i l -97 f l i c k t e s t s (Chance & R o s e c r a n s , 1979), f l i n c h - j u m p t e s t s (Bodnar, K e l l y , S p i a g g i a , & Glusman, 1978), h o t - p l a t e t e s t s (Amir & A m i t , 1978), and operant shock t h r e s h o l d t e s t s (Bodnar, K e l l y , B r u t u s , Mansour, & Glusman, 1978). The a n t i n o c i c e p t i v e e f f e c t s of t h e s e t r e a t m e n t s have been v a r i o u s l y found t o e x i s t f o r p e r i o d s of 5 (e.g. B u c k e t t , 1979) t o 120 min (Bodnar, K e l l y , & Glusman, 1978) f o l l o w i n g t e r m i n a t i o n of the s t r e s s o r . Mechanisms of S t r e s s - I n d u c e d A n a l g e s i a Much of the r e s e a r c h d i r e c t e d a t the p h y s i o l o g i c a l mechanisms of s t r e s s - i n d u c e d a n a l g e s i a i n v o l v e s the p o s s i b l e r o l e of endogenous o p i a t e p e p t i d e s ( e n d o r p h i n s ) i n endogenous p a i n m o d u l a t i o n . The e n d o r p h i n h y p o t h e s i s of p a i n m o d u l a t i o n a r i s e s from an e x t r e m e l y l a r g e body of l i t e r a t u r e d e m o n s t r a t i n g t h a t t h e r e a r e s t e r e o s p e c i f i c r e c e p t o r s f o r o p i a t e s i n the c e n t r a l nervous system (Snyder, 1975; Snyder & P e r t , 1975) and t h a t t h e r e a r e a number of endogenous o p i a t e - l i k e p e p t i d e s t h a t b i n d t o t h e s e r e c e p t o r s ( K o s t e r l i t z & Hughes, 1978; Leong Way, 1979; T e r e n i u s , 1978). There a r e t h r e e e n d o r p h i n m o l e c u l e s t h a t are commonly thought t o have a p o s s i b l e r o l e i n endogenous p a i n m o d u l a t i o n ( A d l e r , 1980; Basbaum & F i e l d s , 1978; B i s h o p , 1980; K o s t e r l i t z , 1979). The f i r s t of t h e s e i s B - e n d o r p h i n . B-e n d o r p h i n i s r e s t r i c t e d i n the c e n t r a l nervous system t o the b a s a l hypothalamus and p i t u i t a r y and i s d e r i v e d from B-L i p o p r o t e i n , a p r e c u r s o r common t o B-endorphin and -melanocyte s t i m u l a t i n g hormone ( L i , 1979; R o s s i e r & Bloom, 1979). The r e m a i n i n g two endogenous o p i a t e p e p t i d e s are M e t - e n k e p h a l i n and L e u - e n k e p h a l i n . These m o l e c u l e s a r e s m a l l e r i n s i z e than B-e n d o r p h i n and a r e much more w i d e l y d i s t r i b u t e d t hroughout the 98 nervous system (Kuhar & U h l , 1979). Met- and L e u - e n k e p h a l i n a re g e n e r a l l y found t o c o e x i s t w i t h i n the same s i t e s i n both the CNS and p e r i p h e r y (Kuhar & U h l , 1979). A l t h o u g h t h e r e a r e d i f f e r e n c e s i n d u r a t i o n of a c t i o n , s t r u c t u r e , and l o c a l i z a t i o n of these t h r e e p e p t i d e s (Basbaum & F i e l d s , 1978; B i s h o p , 1980; K o s t e r l i t z , 1979), i n the p r e s e n t c o n t e x t they a r e c o n s i d e r e d t o g e t h e r as a g e n e r a l c l a s s of n e u r o m o d u l a t o r s , the e n d o r p h i n s , u n l e s s d i s t i n c t i o n s are n e c e s s a r y . C o n s i s t e n t w i t h the proposed r o l e of o p i a t e - l i k e p e p t i d e s i n endogenous p a i n m o d u l a t i o n (Basbaum & F i e l d s , 1978; B i s h o p , 1980; K o s t e r l i t z , 1979; L i e b e s k i n d , 1978; T e r e n i u s , 1979), the en d o r p h i n s have been shown t o have d e f i n i t e p a i n m o d u l a t i n g p r o p e r t i e s i n a v a r i e t y of s p e c i e s . B - e n d o r p h i n , when a d m i n i s t e r e d i n t r a v e n o u s l y (Tseng, Loh, & L i , 1977), i n t r a c r a n i a l l y ( R o s s i e r & Bloom, 1979), or i n t r a t h e c a l l y (Yaksh & Henry, 1978) i s c a p a b l e of p r o d u c i n g a n a l g e s i a s i m i l a r t o t h a t produced by morphine. The e n k e p h a l i n s , Met- and L e u - e n k e p h a l i n , a r e a l s o c a p a b l e of p r o d u c i n g a n a l g e s i a upon i n t r a - c r a n i a l a d m i n i s t r a t i o n ( M i l l e r & C u a t r e c a s a s , 1979) a l t h o u g h the a n a l g e s i a produced i s of much s h o r t e r d u r a t i o n than t h a t produced by i n t r a c r a n i a l B - e n d o r p h i n . A l t h o u g h t h e r e i s some doubt as t o whether the e n d o r p h i n s a r e c a p a b l e of p e n e t r a t i n g the b l o o d - b r a i n b a r r i e r when a d m i n i s t e r e d i n t r a v e n o u s l y (Rapoport, K l e e , P e t t i g r e w , & Ohno, 1980), i t i s c l e a r t h a t they a r e c a p a b l e of a n a l g e s i a i n a t l e a s t some cases of exogenous a d m i n i s t r a t i o n ( K a s t i n , J emison, & Coy, 1979; Tseng, Loh, & L i , 1977). Other e v i d e n c e of a r o l e of e n d o r p h i n s i n p a i n m o d u l a t i o n i s somewhat l e s s d i r e c t i n n a t u r e . B r a i n a r e a s t h a t 99 produce a n a l g e s i a when s t i m u l a t e d e l e c t r i c a l l y (Mayer, Wolfe, A k i l , C a r d e r , & L i e b e s k i n d , 1971; Soper, 1976) t e n d t o be the same a r e a s i n which e n d o r p h i n s are c o n c e n t r a t e d (.Basbaum & F i e l d s , 1978; Kuhar & U h l , 1 9 7 9 ) ) . Naloxone, a r e l a t i v e l y pure o p i a t e a n t a g o n i s t , i s a b l e t o a t l e a s t p a r t i a l l y r e v e r s e or b l o c k the a n a l g e s i c e f f e c t s of b r a i n s t i m u l a t i o n i n t h e s e a r e a s ( A k i l , Mayer, & L i e b e s k i n d , 1976). P a t i e n t s i n severe c h r o n i c p a i n have been shown t o have d e c r e a s e d l e v e l s of e n d o r p h i n s i n c e r e b r o - s p i n a l f l u i d (von K n o r r i n g , Almay, Johansson, & T e r e n i u s , 1978) and females of the s e v e r a l s p e c i e s have been shown t o have h i g h l y e l e v a t e d plasma l e v e l s of e n d o r p h i n s at p a r t u r i t i o n ( C s o n t o s , R u s t , H o l l t , Mahr, Kromer, & Teschemacher, 1979; G i n t z l e r , 1980; Torda, 1978). In a d d i t i o n , severe p h y s i o l o g i c a l s t r e s s has a l s o been shown t o i n c r e a s e c e n t r a l nervous system e n d o r p h i n a c t i v i t y and t o produce a s i g n i f i c a n t degree of a n a l g e s i a i n subsequent t e s t s ( A k i l , Madden, P a t r i c k , & B a r c h a s , 1976; Chance, White, Krynock, & R o s e c r a n s , 1978). The p o s s i b l e mechanism f o r s t r e s s - i n d u c e d a n a l g e s i a seems c l e a r : s t r e s s i n d u c e s a r e l e a s e of e n d o r p h i n s and t h i s i n c r e a s e d a c t i v i t y i n endogenous o p i a t e p e p t i d e systems produces a n a l g e s i a i n a manner s i m i l a r t o the a n a l g e s i a produced by exogenous o p i a t e a d m i n i s t r a t i o n . In o r d e r t o v a l i d a t e the e n d o r p h i n model of s t r e s s - i n d u c e d a n a l g e s i a , a t l e a s t two commonly a c c e p t e d c r i t e r i a must be met (Sawynok, P i n s k y , & L a B e l l a , 1979). The s t r e s s - i n d u c e d a n a l g e s i a e f f e c t s h o u l d be r e v e r s e d or b l o c k e d w i t h the use of a s p e c i f i c o p i a t e a n t a g o n i s t , . and i t s h o u l d d i s p l a y c r o s s -t o l e r a n c e w i t h morphine. Both of t h e s e c r i t e r i a must be met i n 100 o r d e r t o i n f e r t h a t the s t r e s s - i n d u c e d a n a l g e s i a e f f e c t i s o p e r a t i n g t h r o u g h an o p i a t e mechanism. The use of an a n t a g o n i s t d r u g , which presumably o c c u p i e s the r e c e p t o r s i t e s (Snyder, 1975; Snyder & P e r t , 1975), e s t a b l i s h e s a c t i o n on an o p i a t e r e c e p t o r and the c r o s s - t o l e r a n c e e s t a b l i s h e s the common mechanism of a c t i o n of s t r e s s - i n d u c e d and o p i a t e a n a l g e s i a . The SIA phenomenon does not c o n s i s t e n t l y meet e i t h e r of these c r i t e r i a . Chesher and Chan (1977) and B u c k e t t (1979) have shown t h a t a n a l g e s i a i n d u c e d by f o o t s h o c k i s both r e v e r s i b l e by naloxone and shows c r o s s - t o l e r a n c e w i t h morphine. Bodnar, K e l l y , and Glusman (1979) have shown t h a t 2-deoxy-D-glucose a n a l g e s i a shows c r o s s - t o l e r a n c e w i t h morphine but i s l i t t l e a f f e c t e d by naloxone a d m i n i s t r a t i o n . Other s t u d i e s have demonstrated a n a l g e s i c e f f e c t s t h a t a r e n e i t h e r a f f e c t e d by naloxone a d m i n i s t r a t i o n nor show c r o s s - t o l e r a n c e w i t h morphine (e.g. Chance & R o s e c r a n s , 1979a, 1979b). T h i s i n a b i l i t y t o i m p l i c a t e endogenous o p i a t e p e p t i d e s i n a l l forms of SIA has l e d t o the f o r m u l a t i o n of a d u a l mechanism h y p o t h e s i s . T h i s h y p o t h e s i s ( e . g . Bodnar, K e l l y , & Glusman, 1979; Bodnar, Zimmerman, N i l a v e r , Mansour, Thomas, K e l l y , & Glusman, 1980.; S p i a g g i a , Bodnar, K e l l y , & Glusman, 1979) s u g g e s t s t h a t t h e r e a r e two forms of endogenous p a i n m o d u l a t i o n systems a c t i v a t e d by s t r e s s , one an o p i a t e mechanism and the o t h e r a n o n - o p i a t e mechanism. These mechanisms may be a c t i v a t e d e i t h e r i n d e p e n d e n t l y , or t o g e t h e r and would thus e x p l a i n the i n c o n s i s t e n t f i n d i n g s . For example, i f naloxone i s i n e f f e c t i v e i n r e v e r s i n g or b l o c k i n g a s t r e s s - i n d u c e d a n a l g e s i c e f f e c t , one might i n f e r t h a t the a n a l g e s i c mechanism o p e r a t i n g i s n o n - o p i a t e 101 i n n a t u r e . A l t h o u g h t h i s h y p o t h e s i s may e x p l a i n the a n a l g e s i c a c t i o n s of d i f f e r e n t s t r e s s o r s , i t a l s o has some i m p l i c a t i o n s f o r the use of the term ' s t r e s s ' i n a g e n e r a l sense as a u n i t a r y phenomenon i n i n d u c i n g a n a l g e s i a . Commonly a c c e p t e d d e f i n i t i o n s u s u a l l y d e f i n e s t r e s s i n terms of p h y s i o l o g i c a l v a r i a b l e s ( L e s c h n e r , 1978; S e l y e , 1956). That i s , a s t r e s s o r i s any event t h a t produces a supra-normal a c t i v a t i o n of the p i t u i t a r y - a d r e n a l a x i s and a d r e n a l m e d u l l a r y system (e.g. L e s c h n e r , 1978; Mason , 1968). The presence and magnitude of t h i s p h y s i o l o g i c a l response i s thought t o r e f l e c t the p resence and magnitude of the ' s t r e s s ' on the organism ( e . g . see B u r c h f i e l d , Woods, & E l i c h , 1980; P f i s t e r , 1979). I t i s c l e a r from the d a t a d i s c u s s e d above t h a t a l t h o u g h the e n v i r o n m e n t a l e v e n t s used t o induce a n a l g e s i a a r e s t r e s s o r s by the p r e s e n t d e f i n i t i o n , t h e r e i s no c o n s i s t e n t a c t i v a t i o n of a s i n g l e p a i n m o d u l a t i o n system by t h e s e s t r e s s o r s . In f a c t , t h e r e a r e s t r e s s o r s such as exposure t o e t h e r and h o r i z o n t a l o s c i l l a t i o n t h a t do not produce any a n a l g e s i c e f f e c t a t a l l (Hayes, Bennet, Newlon, & Mayer, 1978). In terms of the mechanisms of s t r e s s - i n d u c e d a n a l g e s i a t h e n , i t appears t h a t s t r e s s may a c t i v a t e b oth an o p i a t e and n o n - o p i a t e p a i n m o d u l a t i o n system, one or the o t h e r of t h e s e systems, or n e i t h e r system a t a l l . The purpose of S e c t i o n I I I was t o e v a l u a t e the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n terms of the mechanisms proposed f o r the s t r e s s - i n d u c e d a n a l g e s i a phenomenon. A l t h o u g h as d i s c u s s e d above, s t r e s s may not be s u f f i c i e n t f o r the appearance of an a n t i n o c i c e p t i v e reponse or the a c t i v a t i o n 102 of a p a r t i c u l a r p a i n m o d u l a t i n g mechanism, i t does appear n e c e s s a r y f o r the appearance of a s t r e s s - i n d u c e d a n a l g e s i c e f f e c t . For the a n t i n o c i c e p t i v e e f f e c t of abnormal motion t o be viewed w i t h i n the s t r e s s - i n d u c e d a n a l g e s i a paradigm, i t would seem n e c e s s a r y t o show a ' s t r e s s o r ' e f f e c t of abnormal v e s t i b u l a r s t i m u l a t i o n . In humans, i t seems c l e a r t h a t abnormal v e s t i b u l a r s t i m u l a t i o n produces an a c t i v a t i o n of the p i t u i t a r y - a d r e n a l a x i s and o t h e r p h y s i o l o g i c a l e f f e c t s c o n s i s t e n t w i t h the d e f i n i t i o n of s t r e s s . Humans s u b j e c t e d t o abnormal v e s t i b u l a r s t i m u l a t i o n show e l e v a t e d plasma a d r e n a l s t e r o i d l e v e l s , i n c r e a s e d u r i n a r y s t e r o i d m e t a b o l i t e l e v e l s , and i n c r e a s e d p r o l a c t i n and growth hormone s e c r e t i o n (Eversman, Gottsman, U h l i c h , U l b r e c h t , von Werder, & S c r i b a , 1978; Reason & Brand, 1975). In a n i m a l s , i n c r e a s e d l e v e l s of plasma v a s o p r e s s i n and a d r e n a l s t e r o i d s have been found i n the c a t d u r i n g motion i n d u c e d i l l n e s s (Fox, K i e l , Daunton, Thomson, D i c t o r , & Chee, 1980). The e x p e r i m e n t s d e s c r i b e d below were d e s i g n e d t o e v a l u a t e the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n terms of the mechanisms proposed f o r SIA. P a r t i c u l a r a t t e n t i o n t h e n , was d i r e c t e d a t a t t e m p t i n g t o d i s c r i m i n a t e the p o s s i b l e i nvolvement of o p i a t e or n o n - o p i a t e mechanisms of the m o t i o n - i n d u c e d a n a l g e s i c e f f e c t . T h i s p o s s i b i l i t y was t e s t e d i n terms of the two c r i t e r i a d i s c u s s e d above: r e v e r s a l by an o p i a t e a n t a g o n i s t and the development of c r o s s - t o l e r a n c e w i t h morphine. Experiment 9 The purpose of Experiment 9 was t o i n v e s t i g a t e a p o s s i b l e 103 mechanism of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . I f t h i s e f f e c t i s mediated by endogenous o p i a t e s , then the a n t i n o c i c e p t i v e e f f e c t s h o u l d be b l o c k e d or a t t e n u a t e d i f the r a t i s p r e - t r e a t e d w i t h an o p i a t e a n t a g o n i s t drug p r i o r t o exposure t o abnormal m o t i o n . O p i a t e a n t a g o n i s t s a r e thought t o occupy the o p i a t e r e c e p t o r s i t e s on the neuron and e x e r t v a r y i n g degrees of o p i a t e - l i k e a c t i o n s t h e m s e l v e s (Snyder, 1975; Snyder & P e r t , 1975). Some o p i a t e a n t a g o n i s t s , such as naloxone and n a l t r e x o n e , a r e r e l a t i v e l y 'pure' a n t a g o n i s t s i n t h a t they b l o c k o p i a t e a c t i o n a t the r e c e p t o r l e v e l but e x e r t few i f any o p i a t e -l i k e a c t i o n s t h e m s e l v e s (Snyder, 1975; Snyder & Mathysse, 1975; Snyder & P e r t , 1975). A c c o r d i n g l y , r a t s were p r e - t r e a t e d w i t h v a r y i n g doses of an o p i a t e a n t a g o n i s t p r i o r t o exposure t o the abnormal motion t r e a t m e n t and s u b s e q u e n t l y t e s t e d i n the h o t - w a t e r t a i l w i t h d r a w a l t e s t f o r a n t i n o c i c e p t i o n . METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 60 male hooded r a t s . The r a t s weighed between 300 and 400 gm and were group housed i n hanging w i r e cages under a r e v e r s e d 12 hr l i g h t / d a r k c y c l e . Food and water were f r e e l y a v a i l a b l e . P r o c e d u r e F i v e groups of 12 r a t s each were i n j e c t e d w i t h one of f o u r d i f f e r e n t doses (.125 mg/kg, .25 mg/kg, .50 mg/kg, 1.0 mg/kg) of naloxone h y d r o c h l o r i d e (Endo L a b o r a t o r i e s ) or the v e h i c l e o n l y . The naloxone h y d r o c h l o r i d e was d i s s o l v e d i n s t e r i l e s a l i n e s o l u t i o n (.9% w/v) such t h a t a l l groups r e c e i v e d an e q u i v a l e n t 104 i n j e c t i o n volume (1 m l / k g ) . A l l drug and v e h i c l e t r e a t m e n t s were a d m i n i s t e r e d ( i . p . ) 15 min p r i o r t o t e s t i n g . S i x r a t s from each of the naloxone or v e h i c l e groups were s u b j e c t e d t o the s w i n g i n g motion (30 swings) d e s c r i b e d p r e v i o u s l y and the r e m a i n i n g s i x r e c e i v e d r e s t r a i n t o n l y . The e x p e r i m e n t a l d e s i g n was thus a 2 X 5 f a c t o r i a l w i t h motion or r e s t r a i n t and naloxone dose as the two f a c t o r s . Each r a t was p l a c e d i n a r e s t r a i n i n g tube and underwent the motion t r e a t m e n t or an e q u i v a l e n t p e r i o d of r e s t r a i n t 15 min a f t e r the drug i n j e c t i o n . Immediately f o l l o w i n g the motion or r e s t r a i n t t r e a t m e n t , a hot - w a t e r t a i l w i t h d r a w a l t e s t of a n a l g e s i a was con d u c t e d . R a t s were i n d i v i d u a l l y t e s t e d and the o r d e r of t e s t i n g was c o u n t e r b a l a n c e d a c r o s s groups. RESULTS As may be seen i n F i g u r e 15, naloxone h y d r o c h l o r i d e a t doses of .5 and 1.0 mg/kg appeared t o b l o c k the a n t i n o c i c e p t i v e e f f e c t of motion shown i n the v e h i c l e i n j e c t e d c o n t r o l s and i n th o s e a n i m a l s t r e a t e d w i t h .125 mg/kg nal o x o n e . A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of motion (F=84.73, d f = l / 5 0 , p<.05), a s i g n i f i c a n t dose e f f e c t (F=19.75, df=4/50, p<.05), and a s i g n i f i c a n t motion by dose i n t e r a c t i o n (F=16.68, df=4/50, p<.05). Post-hoc a n a l y s i s (Tukey) i n d i c a t e d t h a t of the f i v e n aloxone and v e h i c l e g roups, o n l y the .5 and 1.0 mg/kg groups d i d not d i f f e r s i g n i f i c a n t l y w i t h r e s p e c t t o t a i l w i t h d r a w a l l a t e n c i e s i n the swing and r e s t r a i n t c o n d i t i o n s , t h u s c o n f i r m i n g the b l o c k i n g a c t i o n of naloxone i n the s e groups. In the r e s t r a i n t c o n d i t i o n , t a i l w i t h d r a w a l l a t e n c i e s d i d not d i f f e r s i g n i f i c a n t l y among the v e h i c l e and n a l o x o n e - i n j e c t e d 105 FIGURE .15. E f f e c t s of v a r i o u s doses on naloxone h y d r o c h l o r i d e on the mot i o n - i n d u c e d a n a l g e s i a phenomenon i n Experiment 9. Tail Withdrawal Latency (sec) o - ' M u ^ o i o i s a i t o o • 1 1 1 1 1 ' 1 • • H 107 g r oups. DISCUSSION The p r e s e n t r e s u l t s i n d i c a t e t h a t p r e t r e a t m e n t w i t h the o p i a t e a n t a g o n i s t naloxone h y d r o c h l o r i d e produces a dose-dependent b l o c k a d e or r e v e r s a l of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . At doses of .5 and 1.0 mg/kg, t h i s r e v e r s a l was t o t a l and the ' a n t i n o c i c e p t i v e e f f e c t of abnormal motion was c o m p l e t e l y b l o c k e d . T h i s r e v e r s a l of the a n t i n o c i c e p t i v e e f f e c t i s c o n s i s t e n t w i t h the invol v e m e n t of an endogenous o p i a t e mechanism i n the p r o d u c t i o n and maintenance of t h i s a n t i n o c i c e p t i v e e f f e c t . T h i s e v i d e n c e does not c o n c l u s i v e l y i m p l i c a t e an endogenous o p i a t e p a i n m o d u l a t i o n system. Naloxone, i n a d d i t i o n t o i t s o p i a t e a n t a g n o n i s t a c t i o n , appears t o have o t h e r p h a r m a c o l o g i c a l e f f e c t s (Sawynok, P i n s k y , & L a B e l l a , 1979). I t i s p o s s i b l e t h a t the b l o c k i n g or r e v e r s i n g e f f e c t of naloxone on the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s due t o an a c t i o n of nal o x o n e o t h e r than i t s a c t i o n on the o p i a t e r e c e p t o r . I t i s f o r t h i s reason t h a t Sawynok, P i n s k y , and L a B e l l a (1979) have s u g g e s t e d t h a t naloxone r e v e r s a l i s a n e c e s s a r y but not a s u f f i c i e n t c r i t e r i o n f o r i m p l i c a t i n g an o p i a t e mechanism. Other a u t h o r s however, appear t o d i s a g r e e ( e.g. Fanselow, 1979; Fanselow & B o l l e s , 1979). One means of d i f f e r e n t i a t i n g between an o p i a t e and non-o p i a t e mechanism would be t o demonstrate a d i s s o c i a t i o n between the e f f e c t s of naloxone on a n t i n o c i c e p t i v e e f f e c t s produced by two d i f f e r e n t s t r e s s o r s : c o l d - w a t e r swimming-induced a n t i n o c i c e p t i o n , a p u t a t i v e n o n - o p i a t e s t r e s s - i n d u c e d a n a l g e s i a 108 (Bodnar, K e l l y , S t e i n e r , & Glusman, 1978) and abnormal motion-induced a n t i n o c i c e p t i o n , a p u t a t i v e o p i a t e a n a l g e s i a mechanism. Exper iment 10 Experiment 10 was an attempt t o d i s s o c i a t e the e f f e c t s of naloxone on two forms of s t r e s s - i n d u c e d a n a l g e s i a : one produced by abnormal motion and the o t h e r produced by c o l d - w a t e r swimming. A n a l g e s i a produced by c o l d - w a t e r swimming has been suggested t o be mediated by a n o n - o p i a t e mechanism and i s r e l a t i v e l y u n a f f e c t e d by naloxone t r e a t m e n t (Bodnar et a l . , 1980; S p i a g g i a e t a l . , 1979). I f the a n t i n o c i c e p t i v e e f f e c t s of abnormal motion and c o l d - w a t e r swimming were d i f f e r e n t i a l l y a f f e c t e d by n a l o x o n e , one c o u l d argue t h a t the i n h i b i t o r y e f f e c t s of naloxone on a n a l g e s i a produced by abnormal motion i s due t o a f a c t o r o t h e r than some n o n s p e c i f i c e f f e c t of naloxone (Sawynok, P i n s k y , & L a B e l l a , 1979). METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 60 male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 300 gm a t t e s t i n g . s e r v e d as s u b j e c t s i n the p r e s e n t e x p e r i m e n t . A l l s u b j e c t s were housed i n groups and were, p u r c h a s e d and m a i n t a i n e d as d e s c r i b e d p r e v i o u s l y . P r o c e d u r e On each of 3 days p r i o r t o t e s t i n g , a l l s u b j e c t s were a c c l i m a t e d t o the r e s t r a i n i n g tubes f o r a 5 min p e r i o d . On the f o u r t h day, 20 r a t s were randomly a s s i g n e d t o one of t h r e e c o n d i t i o n s : m o t i o n , r e s t r a i n t , or c o l d - w a t e r swim. Ten a n i m a l s 109 from each group r e c e i v e d an i n j e c t i o n ( i . p . ) of naloxone h y d r o c h l o r i d e (5 mg/kg) and the r e m a i n i n g 10 a n i m a l s r e c e i v e d i n j e c t i o n s of the s t e r i l e s a l i n e v e h i c l e . T h i s h i g h dose of naloxone was chosen i n an e f f o r t t o extend the dose response r e l a t i o n s h i p of Experiment 9 and t o ensure the a n t i n o c i c e p t i v e e f f e c t of motion would be t o t a l l y b l o c k e d . The d e s i g n of the experiment was thus a 2 X 3 f a c t o r i a l . The a p p r o p r i a t e t r e a t m e n t was a d m i n i s t e r e d 15 min f o l l o w i n g the naloxone or v e h i c l e i n j e c t i o n . In the motion c o n d i t i o n , each r a t was s u b j e c t e d t o the s w i n g i n g motion used p r e v i o u s l y (30 s w i n g s ) . In the r e s t r a i n t c o n d i t i o n , each r a t was p l a c e d i n the r e s t r a i n i n g tube f o r an amount of time e q u i v a l e n t t o t h a t r e q u i r e d t o a d m i n i s t e r the motion t r e a t m e n t ( a p p r o x i m a t e l y 30 s e c ) . In the c o l d - w a t e r swim c o n d i t i o n , the r a t s were p l a c e d i n a 36.5 cm deep, 34 cm diam tank c o n t a i n i n g 22 cm of c o n s t a n t l y c i r c u l a t i n g c o l d water (12° C ) . The a n i m a l s remained i n the water f o r 2.5 min (Bodnar, K e l l y , Thomas, & Glusman, 1980) and were then removed and p l a c e d i n a r e s t r a i n i n g tube f o r an a d d i t i o n a l 2.5 min. Immediately f o l l o w i n g the a d m i n i s t r a t i o n of t h e s e t r e a t m e n t s , the h o t - w a t e r t a i l w i t h d r a w a l t e s t f o r a n a l g e s i a was conducted and t a i l w i t h d r a w a l l a t e n c i e s r e c o r d e d . In a d d i t i o n , b a l a n c e beam t e s t s were a d m i n i s t e r e d t o the r a t s i n the motion and r e s t r a i n t groups t o determine the p o s s i b l e e f f e c t s of naloxone on v e s t i b u l a r f u n c t i o n i n g . RESULTS AND DISCUSSION The r e s u l t s of Experiment 10 a r e shown i n F i g u r e 16. As shown by the f i g u r e , naloxone appeared t o b l o c k the a n t i n o c i c e p t i v e e f f e c t s of both abnormal motion and c o l d - w a t e r 110 FIGURE 16. R e s u l t s of Experiment 10 i l l u s t r a t i n g d i f f e r e n t i a l e f f e c t s of naloxone (5 mg/kg) on t a i l w i t h d r a w a l l a t e n c i e s i n m o t i o n , r e s t r a i n t , and c o l d - w a t e r swim (CW SWIM) t r e a t m e n t s . I l l > o z LU 9 8H 7 6 4 5 4-1 < Q I != 3-1 2J 1 4 JL SALINE Q NALOXONE I x MOTION RESTRAINT CW SWIM 112 swimming. A p r i o r i comparisons ( t - t e s t ) i n d i c a t e d a s i g n i f i c a n t e f f e c t of naloxone i n the motion (t=2.45, df=17, p<.05) and c o l d - w a t e r swim (t=2.45, df=18, p<.05) c o n d i t i o n s , but not i n the r e s t r a i n t c o n d i t i o n (t=.35, df=18, p>.05). Subsequent a n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of naloxone (F=6.6, d f = l / 5 4 , p<.05), a s i g n i f i c a n t e f f e c t of type of treatment (F=5.76, df=2/54, p<.05), but the i n t e r a c t i o n term was not s i g n i f i c a n t (F=.99, df=2/54, p>.05). Post hoc comparisons (Tukey) i n d i c a t e d t h a t i n the n a l o x o n e - i n j e c t e d groups, r e s t r a i n t , c o l d - w a t e r swim, and motion group s c o r e s d i d not d i f f e r (p>.05). In the s a l i n e - i n j e c t e d groups, the motion and c o l d - w a t e r swim groups d i d not d i f f e r from each o t h e r but both had s i g n i f i c a n t l y g r e a t e r t a i l w i t h d r a w a l l a t e n c i e s than t h o s e of the r e s t r a i n t group (P<.05). These r e s u l t s c o n f i r m t h a t naloxone h y d r o c h l o r i d e i s c a p a b l e of r e v e r s i n g or b l o c k i n g t h e a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . Naloxone a l s o appeared t o i n h i b i t the development of a n a l g e s i a when r a t s were exposed t o f o r c e d swimming i n c o l d - w a t e r . T h i s i s p a r t i c u l a r l y s u r p r i s i n g because Bodnar, K e l l y , S p i a g g i a , E h r e n b e r g , and Glusman (1978) had f a i l e d t o observe any s u b s t a n t i a l e f f e c t s of naloxone on c o l d -water swim-induced a n a l g e s i a even a t doses as h i g h as 20 mg/kg. I t i s p o s s i b l e however, t h a t p r o c e d u r a l d i f f e r e n c e s c o u l d account f o r t h i s apparent d i s c r e p a n c y . Bodnar e t a l . used c o l d - w a t e r a t 2° C and the r a t s were unable t o touch the bottom of the swim t a n k . In the p r e s e n t s t u d y , the water was somewhat warmer (12° C) and the r a t s were a b l e t o touch the bottom of the swim tank and l e a p b r i e f l y out of the water a l o n g the smooth 113 s i d e s of the tank . L e w i s , Cannon, and L i e b e s k i n d (1980) and J a c k s o n , M a i e r , and Coon (1979) have shown t h a t the r e v e r s i b i l i t y of f o o t s h o c k - i n d u c e d a n a l g e s i a by naloxone v a r i e s w i t h the manner i n which the shock i s a d m i n i s t e r e d and whether the shock i s e s c a p a b l e or i n e s c a p a b l e . A s i m i l a r s i t u a t i o n may have e x i s t e d i n the p r e s e n t experiment and may thus e x p l a i n the f a i l u r e t o d i s s o c i a t e an o p i a t e or n o n - o p i a t e mechanism i n terms of the e f f e c t s of naloxone i n two d i f f e r e n t forms of s t r e s s -i n d u c e d a n a l g e s i a . B a l a n c e s c o r e s A n a l y s i s of the b a l a n c e beam s c o r e s (see F i g u r e 17) i n d i c a t e d no e f f e c t of e i t h e r motion (F=1.21, d f = l / 3 6 , p>.05) or naloxone a d m i n i s t r a t i o n (F=3.94, d f = l / 3 6 , p>.05). C l e a r l y the ' d i z z i n e s s ' or p o s s i b l e v e s t i b u l a r d y s f u n c t i o n s induced by s w i n g i n g or the p o s s i b l e e l i m i n a t i o n of d i z z i n e s s by naloxone do not e x p l a i n e i t h e r the a n t i n o c i c e p t i v e e f f e c t or i t s r e v e r s a l by n a l o x o n e . The p r e s e n t experiment t h e n , has c o n f i r m e d the naloxone s e n s i t i v i t y of the a n t i n o c i c e p t i v e e f f e c t of abnormal mot i o n . W h i l e t h i s i s a n e c e s s a r y c o n d i t i o n , i t i s not s u f f i c i e n t f o r i m p l i c a t i n g an endogenous o p i a t e mechanism (Sawynok, P i n s k y , & L a B e l l a , 1979). Because the naloxone a l s o appeared t o d e c r e a s e t a i l w i t h d r a w a l l a t e n c i e s i n the CWS group, i t was not p o s s i b l e t o d i f f e r e n t i a t e p o s s i b l e o p i a t e from n o n - o p i a t e mechanisms f o r m o t i o n - i n d u c e d a n t i n o c i c e p t i o n . In o r d e r t o de t e r m i n e whether or not m o t i o n - i n d u c e d a n t i n o c i c e p t i o n was.mediated by. an o p i a t e mechanism, i t was n e c e s s a r y t o demonstrate the development of c r o s s - t o l e r a n c e between the a n t i n o c i c e p t i v e e f f e c t s of morphine 114 FIGURE 17. Mean b a l a n c e beam s c o r e s f o r r a t s r e c e i v i n g s a l i n e or naloxone i n the r e s t r a i n t or motion t r e a t m e n t c o n d i t i o n s of Experiment 10. 115 LU DC O O CO < LU 00 LU O < _J < CD SALINE NALOXONE • 1^ RESTRAINT MOTION 116 and m o t i o n . T h i s i s s u e was a d d r e s s e d i n Experiment 11. Experiment 11 Experiment 11 i n v e s t i g a t e d the p o s s i b l e development of c r o s s - t o l e r a n c e between the a n t i n o c i c e p t i v e e f f e c t of abnormal motion and the a n t i n o c i c e p t i v e e f f e c t of morphine. T o l e r a n c e r e f e r s t o the d e c l i n e i n e f f e c t i v e n e s s of a p a r t i c u l a r t r e a t m e n t w i t h r e p e a t e d a d m i n i s t r a t i o n ( J u l i e n , 1975; L e a v i t t , 1974). For example the a n a l g e s i c e f f i c a c y of a p a r t i c u l a r dose of morphine d e c l i n e s over r e p e a t e d a d m i n i s t r a t i o n of the d r u g . C r o s s -t o l e r a n c e between two or more t r e a t m e n t s i n d i c a t e s t h a t once t o l e r a n c e has developed t o a p a r t i c u l a r t r e a t m e n t , then t o l e r a n c e w i l l a l s o e x i s t f o r a n o v e l t r e a t m e n t . I f c r o s s -t o l e r a n c e does d e v e l o p between two t r e a t m e n t s , t h i s would imply t h a t each t r e a t m e n t e x e r t s i t s e f f e c t t h r o u g h a s i m i l a r mechanism (Bodnar, K e l l y , S t e i n e r , & Glusman, 1978; Chance & R o s e c r a n s , 1979; P e r t & Maxey, 1975; Sawynok, P i n s k y , & L a B e l l a , 1979). For example, i n an organism made t o l e r a n t t o morphine, demerol w i l l produces l e s s a n a l g e s i a than u s u a l . One can i n f e r t h e n , t h a t b oth of t h e s e drugs e x e r t t h e i r i n d i v i d u a l e f f e c t s t h r o u g h an i d e n t i c a l a c t i o n of the o p i a t e r e c e p t o r . T h i s t e c h n i q u e f o r d e t e r m i n i n g the n a t u r e of a t o l e r a n c e mechanism may a l s o be a p p l i e d t o a n a l g e s i a i n d u c e d by non-p h a r m a c o l o g i c a l means. I f c r o s s - t o l e r a n c e d e v e l o p s between the t r e a t m e n t i n q u e s t i o n and a t r e a t m e n t f o r which the mechanisms a r e i d e n t i f i e d , then i t may be i n f e r r e d t h a t the non-p h a r m a c o l o g i c a l t r e a t m e n t i s e x e r t i n g i t s e f f e c t t h r o u g h the same mechanisms as the known t r e a t m e n t . In the case of the 117 a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n , i f the a n t i n o c i c e p t i v e e f f e c t i s mediated through an endogenous o p i a t e mechanism, then c r o s s - t o l e r a n c e s h o u l d d e v e l o p between abnormal motion and exogenous o p i a t e a d m i n i s t r a t i o n . The purpose of the p r e s e n t experiment t h e n , was t o examine the p o s s i b l e development of c r o s s - t o l e r a n c e between abnormal motion and morphine a d m i n i s t r a t i o n . METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 40 n a i v e male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 350 gm. S u b j e c t s were housed i n groups and were purchased and o t h e r w i s e m a i n t a i n e d as d e s c r i b e d p r e v i o u s l y . P r ocedure The experiment c o n s i s t e d of two c o n s e c u t i v e phases: f i r s t , a c h r o n i c phase d u r i n g which the development of t o l e r a n c e t o abnormal motion and morphine was a s s e s s e d , and second, an a c u t e t e s t phase d u r i n g which p o s s i b l e c r o s s - t o l e r a n c e between the t r e a t m e n t s was a s s e s s e d . C h r o n i c phase. Ten a n i m a l s were randomly a s s i g n e d t o each of the f o u r t r e a t m e n t c o n d i t i o n s : abnormal m o t i o n , r e s t r a i n t , morphine, or morphine v e h i c l e . The abnormal motion used was the s w i n g i n g motion (30 swings) used p r e v i o u s l y . The r e s t r a i n t t r e a t m e n t c o n s i s t e d of p l a c i n g the r a t i n the r e s t r a i n i n g tube f o r a p e r i o d of time e q u i v a l e n t t o the d u r a t i o n of the s w i n g i n g m o t i o n . Immediately f o l l o w i n g the motion or r e s t r a i n t t r e a t m e n t , a h o t - w a t e r t a i l w i t h d r a w a l t e s t f o r a n a l g e s i a was c o n d u c t e d . Morphine s u l f a t e (7.5 mg/kg) was d i s s o l v e d i n 118 s t e r i l e s a l i n e (.9% w/v) i n a c o n c e n t r a t i o n of 7.5 mg/ml and a d m i n i s t e r e d ( i . p . ) 15 min p r i o r t o a n a l g e s i a t e s t i n g i n the h o t-water t a i l w i t h d r a w a l t e s t . In the v e h i c l e c o n d i t i o n , a body weight dose of the s a l i n e v e h i c l e was a d m i n i s t e r e d 15 min p r i o r t o a n a l g e s i a t e s t i n g . Each t r e a t m e n t was a d m i n i s t e r e d a t 24 hr i n t e r v a l s f o r 6 days. The r e p e a t e d t e s t i n g i n the morphine and abnormal motion groups a l l o w e d the development of t o l e r a n c e over time t o be examined. The i n c l u s i o n of the r e s t r a i n t and v e h i c l e c o n d i t i o n s a l l o w e d the e l i m i n a t i o n of n o n - s p e c i f i c f a c t o r s t h a t may have a f f e c t e d the a n a l g e s i a measures o b t a i n e d and a l s o a l l o w e d the p r e s e nce and magnitude of the a n a l g e s i a produced by each of t h e s e t r e a t m e n t s t o be a s s e s s e d . The development of t o l e r a n c e was demonstrated by comparing s c o r e s o b t a i n e d i n each t r e a t m e n t c o n d i t i o n on Day 1 t o the r e s p e c t i v e s c o r e s on Day 6 u s i n g a p r i o r i comparisons ( t - t e s t f o r dependent measures). Acute t e s t phase. On the day f o l l o w i n g the c h r o n i c t r e a t m e n t phase, the a c u t e c r o s s - t o l e r a n c e t e s t phase was begun. A l l 40 a n i m a l s i n the f o u r c h r o n i c t r e a t m e n t s were t e s t e d f o r a n t i n o c i c e p t i o n i n a n o-treatment b a s e l i n e c o n d i t i o n , the abnormal motion c o n d i t i o n , and the morphine c o n d i t i o n . The no-t r e a t m e n t b a s e l i n e t e s t was i n c l u d e d t o ensure t h a t t h e r e were no r e s i d u a l e f f e c t s > of the p r e v i o u s c h r o n i c t r e a t m e n t s or t h a t the t a i l w i t h d r a w a l r e f l e x had i n any way been a l t e r e d . In the a c u t e motion t e s t , a l l a n i m a l s were i n d i v i d u a l l y s u b j e c t e d t o the s w i n g i n g motion used i n the c h r o n i c phase of the e x p e r i m e n t . T a i l w i t h d r a w a l l a t e n c i e s were taken i m m e d i a t e l y f o l l o w i n g the c e s s a t i o n of m o t i o n . Two hours f o l l o w i n g the a c u t e motion t e s t , 119 the r a t s were i n j e c t e d w i t h 7.5 mg/kg morphine s u l f a t e d i s s o l v e d i n s t e r i l e s a l i n e . Another t a i l w i t h d r a w a l t e s t was conducted 15 min f o l l o w i n g the i n j e c t i o n . A p r i o r i comparisons between the e x p e r i m e n t a l groups and the a p p r o p r i a t e c o n t r o l groups were c o n d u c t e d f o r each of the b a s e l i n e , m o t i o n , and morphine c o n d i t i o n s i n the a c u t e phase. These comparisons were used t o e v a l u a t e the p o s s i b l e development of c r o s s - t o l e r a n c e . I f f o r example, c r o s s - t o l e r a n c e was found to e x i s t between morphine and abnormal m o t i o n , the c h r o n i c morphine group s h o u l d show s i g n i f i c a n t l y l e s s a n t i n o c i c e p t i o n t h a t the c h r o n i c v e h i c l e - i n j e c t e d a n i m a l s . RESULTS C h r o n i c a d m i n i s t r a t i o n phase I t i s c l e a r from F i g u r e 18 t h a t t h e r e was a d e c r e a s e i n t a i l w i t h d r a w a l l a t e n c i e s as a f u n c t i o n of r e p e a t e d a d m i n i s t r a t i o n of morphine and m o t i o n . A p r i o r i c omparisons ( t -t e s t s f o r dependent measures) of Day 1 and 6 s c o r e s i n d i c a t e d t h a t t h i s d e c r e a s e was s i g n i f i c a n t i n the r e p e a t e d morphine c o n d i t i o n (t=3.77, df=8, p<.05) but the change i n t a i l w i t h d r a w a l l a t e n c i e s f a i l e d t o r e a c h s i g n i f i c a n c e i n the r e p e a t e d motion exposure c o n d i t i o n (t=1.72, df=9, p>.05). N e i t h e r the s a l i n e nor r e s t r a i n t c o n d i t i o n s demonstrated any s i g n i f i c a n t change i n t a i l w i t h d r a w a l l a t e n c i e s from Day 1 t o Day 6. The f a i l u r e t o f i n d s i g n i f i c a n t t o l e r a n c e development i n the motion c o n d i t i o n r a i s e s some q u e s t i o n s c o n c e r n i n g the c a p a b i l i t y of the a n t i n o c i c e p t i v e e f f e c t of abnormal motion t o d e v e l o p t o l e r a n c e f o l l o w i n g r e p e a t e d a d m i n i s t r a t i o n . A n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of 120 FIGURE 18. Mean t a i l w i t h d r a w a l l a t e n c i e s f o r r a t s r e c e i v i n g d a i l y a d m i n i s t r a t i o n o f m o r p h i n e , s a l i n e , m o t i o n , o r r e s t r a i n t i n t h e c h r o n i c phase of E x p e r i m e n t 11. The f i g u r e i l l u s t r a t e s t a i l w i t h d r a w a l l a t e n c i e s on t h e f i r s t (DAY 1) and l a s t (DAY 6 ) d a y s o f t h e c h r o n i c a d m i n i s t r a t i o n p h a s e . TAIL WITHDRAWAL LATENCY Csec) 1 ' ' • • • • • • • • • • • • H 2? IZl 122 t r e a t m e n t (F=25.6, df=3/35, p<.05), a s i g n i f i c a n t e f f e c t of r e p e a t e d a d m i n i s t r a t i o n (F=17.03, df=3/35, p<.05), and a s i g n i f i c a n t i n t e r a c t i o n between t h e s e f a c t o r s (F=8.57, df=3/35, p<.05). Post-hoc a n a l y s i s (Tukey) i n d i c a t e d t h a t b o t h the morphine and motion t r e a t m e n t s produced s i g n i f i c a n t a n a l g e s i a when compared t o the s a l i n e and r e s t r a i n t c o n d i t i o n s , r e s p e c t i v e l y (p<.05). The d a t a f o r one a n i m a l i n the r e s t r a i n t c o n d i t i o n were d e l e t e d from t h i s a n a l y s i s i n a c c o r d a n c e w i t h p r o c e d u r e s d e s c r i b e d by L i (1969) f o r o u t l y i n g d a t a p o i n t s . Acute t e s t phase The r e s u l t s of the t h r e e t e s t s i n the a c u t e t e s t phase are i l l u s t r a t e d i n F i g u r e 19. A p r i o r i comparisons ( t - t e s t f o r independent measures) were used i n a l l t h r e e t e s t s t o compare the e x p e r i m e n t a l groups t o t h e i r r e s p e c t i v e c o n t r o l s . B a s e l i n e t e s t . When r a t s i n the f o u r t r e a t m e n t c o n d i t i o n s were t e s t e d i n the no-treatment b a s e l i n e t e s t , no d i f f e r e n c e s were found between the motion and morphine groups when compared t o t h e i r r e s p e c t i v e c o n t r o l groups (motion v e r s u s r e s t r a i n t , t=.51, df=18, p>.05; morphine v e r s u s s a l i n e , t=-1.24, df=17, p>.05) . M o t i o n t e s t . In the a c u t e motion t e s t , b o th the motion and morphine groups were found t o e x h i b i t t a i l w i t h d r a w a l l a t e n c i e s t h a t were s i g n i f i c a n t l y lower than those shown by the a p p r o p r i a t e c o n t r o l groups (motion v e r s u s r e s t r a i n t , t=3.79, df=18, p<.05; morphine v e r s u s s a l i n e , t=2.12, df=17, p<.05). In c o n t r a s t t o the r e s u l t s of the c h r o n i c phase of t h e p r e s e n t e x p e r i m e n t , the a c u t e motion t e s t i n d i c a t e d t h a t r e p e a t e d exposure t o motion d i d produce t o l e r a n c e t o the a n t i n o c i c e p t i v e 123 FIGURE 19. R e s u l t s of the a c u t e t e s t phase of Experiment 11. The f i g u r e i l l u s t r a t e s a no-treatment b a s e l i n e t e s t and the e f f e c t s of abnormal motion and morphine (7.5 mg/kg) i n r a t s t h a t had been c h r o n i c a l l y exposed t o morphine, s a l i n e , m o t i o n , or r e s t r a i n t . TAIL WITHDRAWAL LATENCY Csec) X X \ V X X % X \ H H 00 m m O O DO TJ z m v 3 I 125 e f f e c t s of abnormal m o t i o n . P r i o r r e p e a t e d exposure t o morphine a l s o a t t e n u a t e d the a n t i n o c i c e p t i v e e f f e c t when t h i s group was exposed t o abnormal motion f o r the f i r s t t i m e . Morphine t e s t . In the a c u t e morphine t e s t , the morphine t r e a t m e n t group d i s p l a y e d s i g n i f i c a n t l y lower t a i l w i t h d r a w a l l a t e n c i e s than d i d a n i m a l s t h a t were exposed t o morphine f o r the f i r s t time (t=2.97, df=17, p<.05). P r i o r r e p e a t e d exposure t o motion however, d i d not r e s u l t i n s i g n i f i c a n t c r o s s - t o l e r a n c e t o morphine as the l a t e n c i e s i n the motion group were not s i g n i f i c a n t l y d i f f e r e n t from those e x h i b i t e d by t h e r e s t r a i n t group when both groups were exposed t o morphine (t=.86, df=18, p>.05) . DISCUSSION The r e s u l t s of the c h r o n i c and a c u t e t e s t i n g phases of the p r e s e n t experiment i n d i c a t e t h a t t o l e r a n c e can d e v e l o p t o the a n t i n o c i c e p t i v e e f f e c t s of morphine and abnormal m o t i o n , the degree of a n t i n o c i c e p t i o n produced by each of t h e s e t r e a t m e n t s d e c l i n e d w i t h r e p e a t e d d a i l y t r e a t m e n t s . T h i s e f f e c t was not due t o r e p e t i t i o n of the t a i l w i t h d r a w a l t e s t as n e i t h e r the r e s t r a i n t nor the s a l i n e groups showed any change i n t a i l w i t h d r a w a l l a t e n c i e s over r e p e a t e d a d m i n i s t r a t i o n of the t e s t i n the c h r o n i c phase. Moreover, the f a c t t h a t t a i l w i t h d r a w a l l a t e n c i e s were almost i d e n t i c a l a c r o s s the t r e a t m e n t groups i n the no-treatment b a s e l i n e t e s t i n the a c u t e phase f u r t h e r d emonstrated t h a t the apparent t o l e r a n c e e f f e c t was not due t o a d i r e c t e f f e c t on the i n t e g r i t y of the t a i l w i t h d r a w a l r e f l e x . R e s u l t s of the a c u t e t e s t i n g phase of the p r e s e n t experiment seem t o i m p l i c a t e an endogenous o p i a t e mechanism i n 126 the m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . R a t s t h a t had been made t o l e r a n t t o the a n a l g e s i c e f f e c t s of morphine showed reduced a n t i n o c i c e p t i o n i n response t o motion i n a subsequent t e s t when compared t o groups of a n i m a l s c h r o n i c a l l y exposed t o e i t h e r r e s t r a i n t or s a l i n e i n j e c t i o n s . The t a i l w i t h d r a w a l s c o r e s were v i r t u a l l y i d e n t i c a l i n the c h r o n i c morphine and c h r o n i c motion groups. T h i s c r o s s t o l e r a n c e would suggest t h a t the a n t i n o c i c e p t i v e e f f e c t s of abnormal motion and the a n t i n o c i c e p t i v e e f f e c t s of morphine a r e mediated by s i m i l a r mechanisms ( B u c k e t t , 1979; Sawynok, P i n s k y , & L a B e l l a , 1979). The f a c t t h a t an o p i a t e r e c e p t o r mechanism i s i n v o l v e d i n the a n a l g e s i c e f f e c t of morphine (Snyder & P e r t , 1975) f u r t h e r i n d i c a t e s t h a t the abnormal motion e f f e c t must a l s o i n v o l v e an o p i a t e r e c e p t o r mechanism and hence an endogenous o p i a t e system t h a t i s a c t i v a t e d upon exposure t o the abnormal m o t i o n . A l t h o u g h c r o s s - t o l e r a n c e does appear t o e x i s t between c h r o n i c morphine and a c u t e t e s t i n g w i t h m o t i o n , c r o s s - t o l e r a n c e does not appear t o e x i s t between c h r o n i c motion p r e e x p o s u r e and a c u t e t e s t i n g w i t h morphine. One c o u l d argue t h a t i f t h e r e were a common mechanism of a c t i o n , then c r o s s - t o l e r a n c e s h o u l d e x i s t r e g a r d l e s s of which t r e a t m e n t was c h r o n i c a l l y a d m i n i s t e r e d (see Sawynok, P i n s k y , & L a B e l l a , 1979). T h i s r e c i p r o c a l or s y m m e t r i c a l c r o s s - t o l e r a n c e phenomenon however, would seem t o assume t h a t each t r e a t m e n t a c t i v a t e s the u n d e r l y i n g mechanism t o the same e x t e n t . In f a c t , asymmetric c r o s s - t o l e r a n c e i s not an u n u s u a l f i n d i n g ( e . g . , Brown, Amit, S m i t h , & Rockman, 1979; P e r t & Maxey, 1975). For example, c o n s i d e r the s i t u a t i o n where two d i f f e r e n t doses of the same drug a r e used f o r both the c h r o n i c 127 and a c u t e t e s t i n g phase. I f a h i g h dose of the drug were used c h r o n i c a l l y and t o l e r a n c e d e v e l o p s , one would expect no a n a l g e s i c e f f e c t upon a d m i n i s t r a t i o n of the low dose of the same dru g . I f on the o t h e r hand, the low dose were used t o d e v e l o p t o l e r a n c e , the h i g h dose would l i k e l y s t i l l produce a b e h a v i o u r a l e f f e c t upon ac u t e t e s t i n g . I t would be u n p a r s i m o n i o u s t o argue t h a t the same drug i s a f f e c t i n g two d i f f e r e n t mechanisms a t the two doses, y e t the d a t a would suggest a s y m m e t r i c a l c r o s s - t o l e r a n c e . " R e c i p r o c a l c r o s s -t o l e r a n c e t h e n , would seem t o be an u nnecessary c r i t e r i o n f o r e s t a b l i s h i n g common mechanisms between d r u g s . A s i m i l a r s i t u a t i o n may have e x i s t e d i n the p r e s e n t experiment and would e x p l a i n the l a c k of r e c i p r o c a l c r o s s - t o l e r a n c e between morphine and abnormal m o t i o n . The p r e s e n t experiment t h e n , by d e m o n s t r a t i n g c r o s s -t o l e r a n c e between morphine a d m i n i s t r a t i o n and abnormal motio n , has p r o v i d e d a d d i t i o n a l e v i d e n c e t h a t an endogenous o p i a t e mechanism p l a y s a r o l e i n the a n t i n o c i c e p t i o n i n d uced by abnormal m o t i o n . T h i s f i n d i n g and t h o s e of E x p e r i m e n t s 9 and 10 d e m o n s t r a t i n g t h a t the a n t i n o c i c e p t i v e e f f e c t can be b l o c k e d w i t h the use of a r e l a t i v e l y pure o p i a t e a n t a g o n i s t , f u l f i l the c r i t e r i a d i s c u s s e d e a r l i e r f o r i m p l i c a t i n g an endogenous o p i a t e mechanism i n m o t i o n - i n d u c e d a n t i n o c i c e p t i o n . The m o t i o n - i n d u c e d a n a l g e s i a phenomenon i s perhaps u n u s u a l i n t h a t the mechanism appears r e l a t i v e l y s t r a i g h t f o r w a r d : motion i n d u c e s a r e l e a s e of endogenous o p i a t e p e p t i d e s and t h e s e p e p t i d e s then e x e r t a p a i n m o d u l a t i n g e f f e c t . A l t h o u g h the e v i d e n c e f o r an endogenous o p i a t e mechanism i s s t r o n g , which o p i a t e p e p t i d e s a r e i n v o l v e d 128 and the l o c u s and r e l e a s e mechanisms of these p e p t i d e s i s unknown. A p r e l i m i n a r y i n v e s t i g a t i o n of t h i s q u e s t i o n was undertaken i n Experiment 12. Experiment 12 B-endor p h i n , M e t - e n k e p h a l i n , and L e u - e n k e p h a l i n a r e d i s t r i b u t e d d i f f e r e n t i a l l y t h roughout v a r i o u s g l a n d and organ systems i n the body (Basbaum & F i e l d s , 1978; B i s h o p , 1980; M i l l e r & C u a t r e c a s a s , 1979; R o s s i e r & Bloom, 1979). B-endorphin f o r example, i s p r i m a r i l y r e s t r i c t e d t o the p i t u i t a r y and b a s a l hypothalamus. Met- and L e u - e n k e p h a l i n , on the o t h e r hand, a r e l o c a t e d i n the a d r e n a l c o r t i c e s and the a d r e n a l m e d u l l a ( S c h u l t z b e r g , Lundberg, H o k f e l t , T e r e n i u s , B r a n d t , E l d e , & G o l d s t e i n , 1978; Yang, Hexum, & C o s t a , 1980) as w e l l as b e i n g d i s t r i b u t e d i n some CNS s i t e s (Kuhar & U h l , 1979). I t seems r e a s o n a b l e t o suggest t h a t i f the e n d o r p h i n s a r e i n v o l v e d i n a n a l g e s i a induced by s t r e s s , they would be s t o r e d i n and r e l e a s e d from systems t h a t a r e r e s p o n s i v e t o s t r e s s . Such systems i n c l u d e the CNS i t s e l f and hormonal systems such as the h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l a x i s and the a d r e n a l m e d u l l a r y system (Mason, 1968; S e l y e , 1956). The p r e s e n t experiment f o c u s s e d on the p o s s i b l e i n v o l v e m e n t of the h y p o t h a l a m i c -p i t u i t a r y a x i s and the a d r e n a l m e d u l l a r y system i n the m e d i a t i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . Both of these hormonal systems have been shown t o be e x t r e m e l y r e s p o n s i v e t o p h y s i o l o g i c a l s t r e s s o r s and the p i t u i t a r y - a d r e n a l a x i s has been p r e v i o u s l y i m p l i c a t e d i n some forms of s t r e s s - i n d u c e d a n a l g e s i a . The h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l a x i s responds t o s t r e s s 129 i n the f o l l o w i n g manner ( L e s c h n e r , 1978; L e v i n e , 1972; S e l y e , 1956). A p p l i c a t i o n of a s t r e s s o r causes a r e l e a s e of c o r t i c o t r o p i n r e l e a s i n g f a c t o r (CRF) from the b a s a l hypothalamus which passes t h r o u g h the hypoph y s e a l p o r t a l system t o the a n t e r i o r p i t u i t a r y . From the p i t u i t a r y , a d r e n o c o r t i c o t r o p h i c hormone (ACTH) i s r e l e a s e d i n t o the c i r c u l a t i o n and then s t i m u l a t e s the p r o d u c t i o n and r e l e a s e of s t e r o i d hormones from the a d r e n a l c o r t i c e s ( e . g . , c o r t i c o s t e r o n e , C o r t i s o l ) . These s e c r e t o r y p r o d u c t s e x e r t a n e g a t i v e feedback i n f l u e n c e on CRF r e l e a s e i n the hypothalamus and i n the absence of an ongoing s t r e s s o r , would cause ACTH s e c r e t i o n from the p i t u i t a r y t o ce a s e . These hormonal e v e n t s a r e , of c o u r s e , not the o n l y hormonal e v e n t s t o oc c u r upon a p p l i c a t i o n of a s t r e s s o r . In a d d i t i o n t o a c t i v a t i o n of the p i t u i t a r y - a d r e n a l a x i s , t h y r o i d a c t i v i t y i s s t i m u l a t e d , p r o l a c t i n i s r e l e a s e d from the p i t u i t a r y , and v a r i o u s o t h e r hormonal events occur ( L e s h n e r , 1978). Not o n l y do B-endorphin and ACTH share the same p r e c u r s o r m o l e c u l e ( A d l e r , 1980; L i , 1979; R o s s i e r & Bloom, 1979) but they a r e a l s o l o c a t e d t o g e t h e r i n the p i t u i t a r y ( G o l d s t e i n & Cox, 1977). I t a l s o appears t h a t B-endorphin and ACTH a r e s e c r e t e d s i m u l t a n e o u s l y by the p i t u i t a r y ( G u i l l e m i n , Vargo, R o s s i e r , M i n i c k , L i n g , R i v i e r , V a l e , & Bloom, 1977). A s i t u a t i o n accompanied by ACTH s e c r e t i o n t h e n , may w e l l be accompanied by an i n c r e a s e i n B-endorphin s e c r e t i o n from the p i t u i t a r y . P i t u i t a r y B-endorphin has been i m p l i c a t e d by a number of a u t h o r s i n a v a r i e t y of n o n - p h a r m a c o l o g i c a l p a i n m o d u l a t i o n e f f e c t s . Bodnar and h i s co-workers (Bodnar, Glusman, B r u t u s , 130 S p i a g g i a , & K e l l y , 1979; Bodnar, K e l l y , Mansour, & Glusman, 1979) have shown t h a t hypophysectomy, or removal of the p i t u i t a r y , g r e a t l y d e c r e a s e s the a n a l g e s i a produced by c o l d -water swimming or 2-deoxy-d-Glucose i n a n i m a l s . Amir and Amit (1978) have f u r t h e r demonstrated t h a t hypophysectomy g r e a t l y a t t e n u a t e s the a n a l g e s i a produced by i m m o b i l i z a t i o n i n r a t s . Treatment w i t h dexamethasone, a s y n t h e t i c g l u c o c o r t i c o i d , a t t e n u a t e s the a n a l g e s i a produced by a c u p u n c t u r e (Cheng, Pomeranz, & Yu, 1979). Dexamethasone i s thought t o produce t h i s e f f e c t by m i m i c k i n g a d r e n a l s t e r o i d n e g a t i v e feedback a c t i o n on the hypothalamus and thus d e c r e a s i n g ACTH (and presumably B-en d o r p h i n ) s e c r e t i o n . The o t h e r s t r e s s - s e n s i t i v e hormonal mechanism c o n s i d e r e d here^ i s the a d r e n a l m e d u l l a r y system. T h i s system responds t o s t r e s s by s e c r e t i n g e p i n e p h r i n e ( a d r e n a l i n e ) and n o r e p i n e p h r i n e ( n o r a d r e n a l i n e ) i n t o the c i r c u l a t o r y system. These c a t e c h o l a m i n e s have a v a r i e t y of autonomic e f f e c t s i n c l u d i n g changes i n b l o o d p r e s s u r e , h e a r t r a t e , r e s p i r a t i o n , and g l u c o s e m o b i l i z a t i o n . A l t h o u g h e n d o r p h i n s (Met- and L e u - e n k e p h a l i n ) have been found w i t h i n n e u r o s e c r e t o r y c e l l s i n the a d r e n a l m e d u l l a (Yang, Hexum, & C o s t a , 1980), they have y e t t o be i m p l i c a t e d i n p a i n m o d u l a t i o n . I t i s a l s o p o s s i b l e t h a t the a d r e n a l m e d u l l a r y hormones are i n v o l v e d i n s t r e s s - i n d u c e d a n a l g e s i a i n another manner. Dworkin, F i l e w i c h , M i l l e r and C r a i g m y l e (1979) have r e c e n t l y d e monstrated t h a t a n a l g e s i a may be produced by a c t i v a t i o n of the c a r o t i d r e f l e x by t r e a t m e n t w i t h a sympathomimetic d r u g . A s i m i l a r a n t i n o c i c e p t i v e e f f e c t may be produced i f c a t e c h o l a m i n e s r e l e a s e d by the a d r e n a l 131 m e d u l l a e l i c i t the c a r o t i d r e f l e x i n a s i m i l a r f a s h i o n . One way of t e s t i n g t h e s e hypotheses would be t o a s s e s s the degree of m o t i o n - i n d u c e d a n t i n o c i c e p t i o n f o l l o w i n g removal of the a d r e n a l g l a n d . Removal of the a d r e n a l g l a n d e l i m i n a t e s the feedback i n h i b i t i o n of ACTH s e c r e t i o n and hence produces g r e a t l y i n c r e a s e d s e c r e t i o n of ACTH ( M a r t i n i , M o t t a , & M u l l e r , 1964). I f G u i l l e m i n et a l . (1977) a r e c o r r e c t , i n c r e a s e d ACTH s e c r e t i o n s h o u l d be accompanied by g r e a t l y i n c r e a s e d p i t u i t a r y B-endorphin s e c r e t i o n . T h i s i n c r e a s e i n B-endorphin c o n c e n t r a t i o n s c o u l d have a t l e a s t two d i r e c t r e s u l t s . One p o s s i b l e r e s u l t would be an a n t i n o c i c e p t i v e e f f e c t of adrenalectomy a l o n e as a by- p r o d u c t of i n c r e a s e d ACTH s e c r e t i o n . As t h i s e f f e c t c o u l d mask the e f f e c t of abnormal m o t i o n , a d r e n a l e c t o m i z e d a n i m a l s not s u b j e c t e d t o abnormal motion were i n c l u d e d i n the p r e s e n t e x p e r i m e n t . The second r e s u l t might be the development of t o l e r a n c e t o the a n a l g e s i c e f f e c t s of B-en d o r p h i n s e c r e t e d by the p i t u i t a r y . T o l e r a n c e does d e v e l o p t o the e f f e c t s of exogenously a d m i n i s t e r e d B-endorphin ( A d l e r , 1980; Huidobro-Torp & Leong Way, 1978; K o s t e r l i t z , 1979) and t h i s t o l e r a n c e e f f e c t would a t t e n u a t e any a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n a d r e n a l e c t o m i z e d a n i m a l s . Adrenalectomy would a l s o remove any c o n t r i b u t i o n of a d r e n a l m e d u l l a r y hormones ( c a t e c h o l a m i n e s or e n k e p h a l i n s ) and hence s h o u l d a l s o a t t e n u a t e the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i f the s e s u b s t a n c e s a r e i n v o l v e d . Adrenalectomy a l s o has the advantage of a m i n i m a l d e b i l i t a t i n g e f f e c t on the a n i m a l ( p r o v i d i n g a s a l i n e s o l u t i o n i s a v a i l a b l e ) , a t l e a s t when compared t o the e f f e c t s of hypophysectomy. . The p r e s e n t experiment t h e n , 132 i n v e s t i g a t e d the p o s s i b l e e f f e c t s of a d r e n a l e c t o m y on the a n t i n o c i c e p t i v e e f f e c t s of abnormal m o t i o n . .METHOD S u b j e c t s and s u r g e r y F o r t y male hooded r a t s w e i g h i n g a p p r o x i m a t e l y 350 gm s e r v e d as s u b j e c t s i n the p r e s e n t e x p e r i m e n t . S u b j e c t s were purchased and m a i n t a i n e d i n groups as d e s c r i b e d p r e v i o u s l y . On the day of s u r g e r y , a l l s u b j e c t s were a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l (Nembutal, 50 mg/kg, i . p . ) and randomly a s s i g n e d t o e i t h e r the adrenalectomy (ADREX, n = 20) or sham-adr e n a l e c t o m y (SHAM, n = 20) s u r g i c a l groups. A d r e n a l e c t o m i e s were a c c o m p l i s h e d u s i n g a b i l a t e r a l lumbar approach. The ki d n e y was g e n t l y e x t r a c t e d from the body c a v i t y and the a d r e n a l g l a n d v i s u a l i z e d and removed. The k i d n e y was then r e p l a c e d and the abdominal w a l l and s k i n i n c i s i o n s were c l o s e d w i t h s i l k s u t u r e s . Sham-adrenalectomies were a c c o m p l i s h e d f o l l o w i n g the same pr o c e d u r e e x c e p t the a d r e n a l was me r e l y v i s u a l i z e d . F o l l o w i n g s u r g e r y , a l l a d r e n a l e c t o m i z e d a n i m a l s were a l l o w e d c o n t i n o u s a c c e s s t o .9% s a l i n e s o l u t i o n . F o l l o w i n g b e h a v i o u r a l t e s t i n g , the a n i m a l s were s a c r i f i c e d i n a ca r b o n d i o x i d e chamber and a u t o p s i e s were conducted t o v e r i f y removal of the a d r e n a l g l a n d s . P r o c e d u r e Three weeks f o l l o w i n g s u r g e r y , a time when ACTH s e c r e t i o n i s thought t o be maximal ( M a r t i n i et a l . , 1964), the a d r e n a l e c t o m i z e d and sham-adrenalectomized r a t s were randomly a s s i g n e d t o e i t h e r a motion or r e s t r a i n t t e s t c o n d i t i o n . The e x p e r i m e n t a l d e s i g n was thus a 2 X 2 f a c t o r i a l . On each of 3 133 days p r i o r t o t e s t i n g , a l l r a t s were a c c l i m a t e d t o the r e s t r a i n i n g tubes f o r a p e r i o d of- 5 min. On the day of t e s t i n g , each ADREX or SHAM r a t underwent the a p p r o p r i a t e motion or r e s t r a i n t t r e a t m e n t . The motion used was the s w i n g i n g motion (30 swings) d e s c r i b e d p r e v i o u s l y , whereas the r e s t r a i n t c o n d i t i o n i n v o l v e d a p e r i o d of r e s t r a i n t e q u i v a l e n t t o the motion t r e a t m e n t d u r a t i o n . Immediately f o l l o w i n g motion or r e s t r a i n t , the hot-water t a i l w i t h d r a w a l t e s t f o r a n a l g e s i a was a d m i n i s t e r e d and the t a i l w i t h d r a w a l l a t e n c i e s r e c o r d e d . RESULTS AND DISCUSSION The r e s u l t s of Experiment 12 a r e shown i n F i g u r e 20. I t i s app a r e n t from t h i s f i g u r e t h a t a d r e nalectomy had l i t t l e e f f e c t on e i t h e r b a s e l i n e t a i l w i t h d r a w a l l a t e n c i e s or on the e x p r e s s i o n of the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . A n a l y s i s of v a r i a n c e c o n f i r m e d t h a t a l t h o u g h t h e r e was a s i g n i f i c a n t e f f e c t of motion on t a i l w i t h d r a w a l l a t e n c i e s (F=32.69, d f = l / 2 7 , p<.05), t h e r e was n e i t h e r a s i g n i f i c a n t e f f e c t of adrenalectomy (F=3.12, d f = l / 2 7 , p>.05), nor a s i g n i f i c a n t i n t e r a c t i o n (F=1.52, d f = l / 2 7 , p>.05). Subsequent a u t o p s i e s c o n f i r m e d t h a t the a d r e n a l e c t o m i e s had been complete. These r e s u l t s , a l t h o u g h not c o n c l u s i v e (due t o the problems a s s o c i a t e d w i t h a c c e p t i n g the n u l l h y p o t h e s i s ) , would suggest t h a t t h e r e i s l i t t l e i n v o l v e m e n t of the p i t u i t a r y - a d r e n a l a x i s i n t he mechanisms of the abnormal m o t i o n - i n d u c e d a n t i n o c i c e p t i v e phenomenon. A d r e n a l e c t o m i z e d r a t s showed normal t a i l w i t h d r a w a l l a t e n c i e s i n the r e s t r a i n t c o n d i t i o n and, l i k e t h e sham-a d r e n a l e c t o m i z e d a n i m a l s , demonstrated e l e v a t e d t a i l w i t h d r a w a l l a t e n c i e s as a r e s u l t of exposure t o abnormal m o t i o n . A l t h o u g h 134 FIGURE 20. The e f f e c t s of abnormal motion on t a i l w i t h d r a w a l l a t e n c i e s i n r a t s t h a t had been a d r e n a l e c t o m i z e d (ADREX) or sham-adrenalectomized (SHAM) i n Experiment 12. 135 ADREX SHAM 136 some a u t h o r s (see Gray & G o r z a l k a , 1980) have suggested t h a t t h e r e a r e changes i n sensory t h r e s h o l d s f o l l o w i n g a d r e n a l e c t o m y , such changes were not e v i d e n t i n the p r e s e n t e x p e r i m e n t . Other a u t h o r s ( e . g . , G r e v e r t , Baisman, & G o l d s t e i n , 1978) have c o n f i r m e d t h a t a d r e nalectomy has l i t t l e e f f e c t on a n t i n o c i c e p t i v e mechanisms. I t would seem t h e n , t h a t t h e r e i s no s i m p l e or o b v i o u s r e l a t i o n s h i p between the a d r e n a l - p i t u i t a r y a x i s or the a d r e n a l m e d u l l a r y system and the a n t i n o c i c e p t i v e e f f e c t s of abnormal m o t i o n . The o p i a t e mechanism r e s p o n s i b l e f o r the a n t i n o c i c e p t i v e e f f e c t s of abnormal motion appears t o be l o c a t e d i n the c e n t r a l nervous system r a t h e r than i n the p i t u i t a r y or a d r e n a l g l a n d s . The r e a d e r must be c a u t i o n e d however, t h a t t h i s c o n c l u s i o n i s , t o a l a r g e e x t e n t , based on a n e g a t i v e r e s u l t . 137 G e n e r a l D i s c u s s i o n -_ S e c t i o n I I I The e x p e r i m e n t s d e s c r i b e d i n t h i s s e c t i o n i n d i c a t e t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion r e l i e s on an endogenous p a i n m o d u l a t i o n system t h a t i s o p i a t e i n n a t u r e . The o p i a t e n a t u r e of t h i s mechanism was e s t a b l i s h e d by a p p l y i n g two c r i t e r i a t h a t a r e n e c e s s a r y f o r i m p l i c a t i n g an endogenous o p i a t e mechanism i n a n t i n o c i c e p t i v e phenomena. F i r s t , E x p e r i m e n t s 9 and 10 d e monstrated t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion can be b l o c k e d by the o p i a t e a n t a g o n i s t n a l o x o n e . Second, Experiment 11 demonstrated t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion shows c r o s s - t o l e r a n c e w i t h the a n t i n o c i c e p t i v e e f f e c t s of morphine a d m i n i s t r a t i o n . A l t h o u g h i t seems c l e a r t h a t an o p i a t e mechanism i s i n v o l v e d i n the m e d i a t i o n of t h i s e f f e c t , the e x a c t n a t u r e of t h i s o p i a t e mechanism i s not known. Experiment 12 s u g g ested t h a t the mechanism i s not a p e r i p h e r a l s t r e s s - s e n s i t i v e one; n e i t h e r the p i t u i t a r y - a d r e n a l a x i s nor the a d r e n a l m e d u l l a r y system appear t o i n f l u e n c e the degree of a n t i n o c i c e p t i o n produced by abnormal m o t i o n . I t remains t o be d e t e r m i n e d which endogenous o p i a t e p e p t i d e i s i n v o l v e d i n the m e d i a t i o n of t h i s phenomenon. Both B-endorphin and the e n k e p h a l i n s have been shown t o produce a n t i n o c i c e p t i o n when a d m i n i s t e r e d a c u t e l y and t o l e r a n c e when a d m i n i s t e r e d c h r o n i c a l l y ( A d l e r , 1980; K o s t e r l i t z , 1979; M i l l e r & C u a t r e c a s a s , 1979; R o s s i e r & Bloom, 1979) but t h e r e a r e d i f f e r e n c e s among t h e s e p e p t i d e s . The major d i f f e r e n c e s l i e i n t h e i r s t r u c t u r e , l o c a l i z a t i o n , a n a l g e s i c p o t e n c y , and s t a b i l i t y ( A d l e r , 1980; B i s h o p , 1980). The d i f f e r e n c e s i n s t r u c t u r e and l o c a l i z a t i o n have been d i s c u s s e d 138 p r e v i o u s l y and the d i f f e r e n c e s i n a n a l g e s i c potency and s t a b i l i t y a r e d i s c u s s e d below. I t appears t h a t when B-endorphin or the e n k e p h a l i n s a r e a d m i n i s t e r e d i n t r a c r a n i a l l y or i n t r a v e n o u s l y , B-endorphin has more a n a l g e s i c potency than e i t h e r the e n k e p h a l i n s or morphine when compared on a molar b a s i s ( L i e b e s k i n d , 1978; M i l l e r & C u a t r e c a s a s , 1979; R o s s i e r & Bloom, 1979). In a d d i t i o n , B-e n d o r p h i n has been shown t o be much more s t a b l e than the e n k e p h a l i n s ( B i s h o p , 1980). E n k e p h a l i n s a r e g e n e r a l l y b e l i e v e d t o have e x t r e m e l y s h o r t h a l f l i v e s ( B i s h o p , 1980; Kuhar & U h l , 1979; M i l l e r & C u a t r e c a s a s , 1979) and a r e degraded r a p i d l y upon a d m i n i s t r a t i o n ( K a s t i n , Jemison, & Coy, 1979), p o s s i b l y by e n zymatic d e g r a d a t i o n . S u p p o r t i n g the h y p o t h e s i s t h a t a l o n g - a c t i n g p e p t i d e such as B-endorphin i s not i n v o l v e d i s the f a c t t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion decays q u i c k l y when compared t o o t h e r forms of s t r e s s - i n d u c e d a n a l g e s i a (such as i m m o b i l i z a t i o n or c o l d - w a t e r swim-induced a n a l g e s i a ) and f u r t h e r , does not appear t o be a f f e c t e d by d i s r u p t i o n of the p i t u i t a r y a d r e n a l a x i s . T h i s would suggest t h a t a h i g h l y r e s p o n s i v e , s h o r t - a c t i n g o p i a t e p e p t i d e system such as the e n k e p h a l i n e r g i c system i s i n v o l v e d . U n f o r t u n a t e l y , the p r e s e n t d a t a do not a l l o w t h i s i s s u e t o be f u r t h e r r e s o l v e d . I t would a l s o seem t h a t the o p i a t e a n a l g e s i a mechanism i s not t o n i c a l l y a c t i v e i n the r a t . I f t h i s were so, one would e x p e c t naloxone t o have lo w e r e d t a i l w i t h d r a w a l l a t e n c i e s i n t h e n a l o x o n e - t r e a t e d r e s t r a i n t groups r e l a t i v e t o the v e h i c l e -i n j e c t e d r e s t r a i n t groups of E x p e r i m e n t s 9 and 10. As was shown 139 i n F i g u r e s 15 and 16, t h i s was not the c a s e . T h i s f i n d i n g i s c o n s i s t e n t w i t h the s u g g e s t i o n of G o l d s t e i n (1979) and o t h e r s t h a t o p i a t e p a i n m o d u l a t i o n systems a r e q u i e s c e n t u n t i l a c t i v a t e d by an a p p r o p r i a t e s t i m u l u s . Other r e s e a r c h e r s however, have found t h a t naloxone i s a b l e t o i n c r e a s e the s e n s i t i v i t y of the organism t o n o x i o u s s t i m u l i ( e . g . , Bonnet, A l p e r t , K l i n e r o c k , 1978). G o l d s t e i n (1978) has s u g g ested t h a t these e f f e c t s may w e l l r e p r e s e n t a p r o c e d u r a l a r t i f a c t . I f the a n i m a l s were ' s t r e s s e d ' by the h a n d l i n g and t e s t i n g p r o c e d u r e s i n t h e s e e x p e r i m e n t s , the a p parent decrease i n n o c i c e p t i v e t h r e s h o l d s by naloxone may r e p r e s e n t n o t h i n g more than a s t r e s s -induced e l e v a t i o n of n o c i c e p t i v e t h r e s h o l d s i n the c o n t r o l groups a g a i n s t which the naloxone t r e a t e d groups were e v a l u a t e d . I t would seem th e n , t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s mediated by an endogenous o p i a t e p a i n m o d u l a t i o n system t h a t i s a c t i v a t e d i n response t o abnormal motion but i s not t o n i c a l l y a c t i v e . The f a c t t h a t abnormal motion and hence abnormal v e s t i b u l a r s t i m u l a t i o n a c t i v a t e s an endogenous o p i a t e system t h a t l i b e r a t e s e n d o r p h i n s i n the CNS may have i m p o r t a n t i m p l i c a t i o n s f o r o t h e r e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n . That i s , i t i s p o s s i b l e t h a t some of the o t h e r e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n such as motion s i c k n e s s may be mediated by mechanisms s i m i l a r t o t h o s e of the a n t i n o c i c e p t i v e e f f e c t . Some of t h e s e p o s s i b i l i t i e s were i n v e s t i g a t e d i n S e c t i o n IV. 140 SECTION IV - Other B e h a v i o u r a l E f f e c t s of Abnormal M o t i o n A l t h o u g h the p r e v i o u s s e c t i o n s were almost e x c l u s i v e l y c oncerned w i t h one b e h a v i o u r a l e f f e c t of abnormal m o t i o n , the a n t i n o c i c e p t i v e e f f e c t , t h e r e a r e o t h e r b e h a v i o r a l e f f e c t s of abnormal motion. As d i s c u s s e d p r e v i o u s l y i n the g e n e r a l i n t r o d u c t i o n , motion s i c k n e s s and a p o s s i b l e c a l m i n g e f f e c t may a l s o r e s u l t from exposure t o abnormal motion e n v i r o n m e n t s . The g e n e r a l purpose of S e c t i o n IV was t o f u r t h e r i n v e s t i g a t e these a d d i t i o n a l b e h a v i o u r a l e f f e c t s of abnormal motion and, i n the case of motion s i c k n e s s , t h e i r p o s s i b l e r e l a t i o n s h i p t o the mechanisms of the a n t i n o c i c e p t i v e phenomenon. S i n c e the d i s c o v e r y of the endogenous o p i a t e p e p t i d e s , they have been i m p l i c a t e d i n a wide v a r i e t y of b e h a v i o u r s and b e h a v i o u r a l e f f e c t s i n a d d i t i o n t o t h e i r r o l e i n p a i n m o d u l a t i o n . In a n i m a l s , o p i a t e p e p t i d e s have been i m p l i c a t e d i n s e x u a l b e h a v i o u r (Myers & Baum, 1979; Q u a r a n t o t t i , Corda, P a g l i e t t i , B i g g i o , & Gessa, 1978), p r e f e r e n c e f o r s i g n a l l e d v e r s u s u n s i g n a l l e d shock (Fanselow, 1979), a g g r e s s i v e b e h a v i o u r (Fanselow, Sigmundi, & B o l l e s , 1980), b r a i n s t i m u l a t i o n reward mechanisms ( S t e i n , 1978; S t e i n & B e l l u z i , 1978), l e a r n e d b e h a v i o u r s ( R i g t e r , Hannan, M e s s i n g , M a r t i n e z , Vasquez, J e n s e n , V e l i q u e t t e , & McGaugh, 1980), changes i n open f i e l d b e h a v i o u r (Fanselow & B o l l e s , 1979), and o t h e r b e h a v i o u r a l r e s p o n s e s . In humans, e n d o r p h i n s have been i m p l i c a t e d i n v a r i o u s p s y c h o p a t h o l o g i c a l s t a t e s i n c l u d i n g d e p r e s s i o n ( B e r g e r , 1978), s c h i z o p h r e n i a (Herz, B i a s i n g , E m r i c h , C o r d i n g , A r e e , R o l l i n g , & Z e r s e e n , 1978; T e r e n i u s , 1978), and a n x i e t y ( G r e v e r t & G o l d s t e i n , 1977; G r e v e r t & G o l d s t e i n , 1978). I t would seem 141 t h e n , t h a t the e n d o r p h i n s may have a wider r o l e i n b e h a v i o u r than t h e i r r o l e i n p a i n m o d u l a t i o n would i n d i c a t e . T h i s would suggest t h a t the e n d o r p h i n s may w e l l mediate o t h e r b e h a v i o u r a l e f f e c t s produced by t r e a t m e n t s t h a t a c t i v a t e endogenous o p i a t e systems. The purpose of E x p e r i m e n t s 13 and 14 was t o i n v e s t i g a t e some of the p o s s i b l e i m p l i c t i o n s of a c t i v a t i n g the endogenous o p i a t e system by abnormal m o t i o n . S p e c i f i c a l l y , both e x p e r i m e n t s were concerned w t i h a p o s s i b l e r o l e f o r o p i a t e p e p t i d e s i n the n e u r a l m e d i a t i o n of motion s i c k n e s s i n the r a t . Experiment 15, on the o t h e r hand, i n v e s t i g a t e d a d i f f e r e n t a s p e c t of the b e h a v i o u r a l e f f e c t s of abnormal m o t i o n . T h i s experiment e x p l o r e d the p u t a t i v e " c a l m i n g " . or " a n x i o l y t i c " e f f e c t s of v e s t i b u l a r s t i m u l a t i o n i n a b e h a v i o u r a l t e s t t h a t i s s e n s i t i v e t o a n x i o l y t i c a g e n t s . Exper iment 13 Money (1970) has suggested t h a t the motion s i c k n e s s syndrome i s produced by a c h e m i c a l l i b e r a t e d i n s i g n i f i c a n t amounts d u r i n g exposure t o the motion environment. One i m p l i c a t i o n of t h i s statement i s t h a t i f one c o u l d p r e v e n t the r e l e a s e of t h i s c h e m i c a l or b l o c k i t s e f f e c t a t the s i t e of a c t i o n , one c o u l d t r e a t or e f f e c t i v e l y p r e v e n t motion s i c k n e s s . A t t e m p t s t o c h a r a c t e r i z e the c h e m i c a l m e d i a t o r of motion s i c k n e s s have, f o r the most p a r t , been u n s u c c e s s f u l (Reason & Brand, 1975; Wood, 1979). A wide v a r i e t y of drugs from v a r i o u s p h a r m a c o l o g i c a l c l a s s i f i c a t i o n s have been used i n a t t e m p t s t o p r e v e n t or t r e a t motion s i c k n e s s . These d i f f e r e n t p h a r m a c o l o g i c a l t r e a t m e n t s have met w i t h v a r y i n g degrees of 142 s u c c e s s , but none has proven t o t a l l y e f f e c t i v e (Reason & Brand, 1975; Wood, 1979). The drugs t h a t have been shown t o be e f f e c t i v e i n motion s i c k n e s s do not appear t o e x e r t t h e i r t h e r a p e u t i c e f f e c t s i n terms of t h e i r major p h a r m a c o l o g i c a l a c t i o n s (Wood, 1979). Scopolamine, f o r example, i s an a n t i - c h o l i n e r g i c agent t h a t i s somewhat e f f e c t i v e i n t r e a t i n g motion s i c k n e s s yet o t h e r a n t i c h o l i n e r g i c drugs such as a t r o p i n e have l i t t l e u s e f u l n e s s . The same i s t r u e f o r d i m e n h y d r i n a t e , an a n t i - h i s t a m i n e , and p r o m e t h a z i n e , a p h e n o t h i a z i n e d e r i v a t i v e : o t h e r a n t i - h i s t a m i n e s and o t h e r p h e n o t h i a z i n e s have l i t t l e t h e r a p e u t i c e f f e c t i v e n e s s i n t r e a t i n g motion s i c k n e s s . Thus, t h a t i t may be some common a c t i o n of t h e s e drugs o t h e r than t h e i r main p h a r m a c o l o g i c a l a c t i o n t h a t i s u s e f u l i n the p r e v e n t i o n and t r e a t m e n t of motion s i c k n e s s . T h i s common a c t i o n has y e t t o be c l e a r l y i d e n t i f i e d and hence the c h e m i c a l m e d i a t o r of motion s i c k n e s s remains unknown. There i s e v i d e n c e from a v a r i e t y of s o u r c e s t o suggest t h a t t h i s c h e m i c a l m e d i a t o r of motion s i c k n e s s may be o p i a t e i n n a t u r e . The p r e c e d i n g p o r t i o n s of t h i s t h e s i s have suggested t h a t an o p i a t e mechanism i s a c t i v a t e d as a r e s u l t of complex forms of abnormal m o t i o n . I t a l s o appears t h a t t h e r e i s some r e l a t i o n s h i p between motion s i c k n e s s , v e s t i b u l a r f u n c t i o n , and o p i a t e mechanisms. One of the m y r i a d e f f e c t s of o p i a t e (morphine) a d m i n i s t r a t i o n i n humans i s nausea and v o m i t i n g (Gutner, G o u l d , & Batterman, 1952; J a f f e & M a r t i n , 1975). T h i s nausea and v o m i t i n g i s seen much more f r e q u e n t l y i n ambulatory p a t i e n t s 143 than i n p a t i e n t s who a r e c o n f i n e d t o bed and r e s t r i c t e d i n t h e i r movements. I t appears t h a t v e s t i b u l a r s t i m u l a t i o n and morphine i n t e r a c t i n some manner t o produce t h i s i n c r e a s e d f r e q u e n c y of s i d e e f f e c t s (Gutner et a l . , 1952), p o s s i b l y t h r o u g h t h e i r a c t i o n on a s i m i l a r u n d e r l y i n g mechanism. Money (1970) has a l s o noted t h a t apomorphine-induced nausea and v o m i t i n g i s l e s s p r e v a l e n t i n s u b j e c t s whose movements a r e r e s t r i c t e d . I t i s a l s o known (Money, 1970) t h a t sub-maximal doses of emetic drugs summate or s y n e r g i s e w i t h abnormal motion t o a c c e l e r a t e the development of motion s i c k n e s s . W i t h r e s p e c t t o the nausea and v o m i t i n g i n d uced by morphine a d m i n i s t r a t i o n , Snyder (1977) and Kuhar and U h l (1979) have suggested t h a t t h i s e f f e c t may be due t o the a c t i v a t i o n of a p o o l of o p i a t e r e c e p t o r s l o c a t e d i n the ar e a postrema. T h i s s t r u c t u r e i s s t r o n g l y i m p l i c a t e d i n the c e n t r a l emetic t r i g g e r i n g p r o c e s s e s i n a v a r i e t y of s p e c i e s ( B r i z z e , Ordy, & M e h l e r , 1980; Wang & B o r i s o n , 1952). I f the c e n t r a l emetic mechanisms a r e damaged by l e s i o n i n g , the s u b j e c t i s re n d e r e d i n s e n s i t i v e t o the emetic e f f e c t s of abnormal motion ( B r i z z e e , Ordy, & M e h l e r , 1980; Money, 1970) and v a r i o u s c e n t r a l l y - a c t i n g emetic drugs ( C o i l & G a r c i a , 1977; Wang & B o r i s o n , 1952). The s i g n s and symptoms of motion s i c k n e s s a l s o seem t o bear a s t r o n g resemblance t o the e f f e c t s of morphine t r e a t m e n t . The s i g n s and symptoms of motion s i c k n e s s a r e compared t o those of morphine a d m i n i s t r a t i o n i n Ta b l e 1. Data c o n c e r n i n g the symptoms of motion s i c k n e s s were c o m p i l e d from Reason and Brand (1975) and Money (1970), whereas t h o s e f o r morphine were c o m p i l e d from J a f f e and M a r t i n (1975). I t i s r e a d i l y apparent 144 Tab l e 1. Comparison of some s i g n s and symptoms e l i c i t e d by o p i a t e (morphine) a d m i n i s t r a t i o n and by exposure t o abnormal motion (motion s i c k n e s s ) . The presence or absence of a p a r t i c u l a r symptom i s i n d i c a t e d by Yes or No, and the q u e s t i o n a b l e e x i s t e n c e of a symptom or l a c k of e v i d e n c e f o r a symptom by ?. Symptoms and s i g n s Motion O p i a t e s Nausea Yes Yes V o m i t i n g Yes Yes P a l l o r Yes No - s k i n f l u s h e d C o l d s w e a t i n g Yes Yes S i g h i n g , yawning Yes ? I n c r e a s e d r e s p i r a t i o n Y e s ( ? ) No - d e p r e s s e d P a n t i n g i n dogs Yes Yes D y s p h o r i a Yes Y e s - o c c a s i o n a l l y I n c r e a s e d s a l i v a t i o n Yes No F e e l i n g of body warmth Yes Yes C o n s t i p a t i o n Yes Yes D r o w s i n e s s Yes Yes I n c r e a s e d ADH output Yes Yes EEG changes Yes Yes P u p i l l a r y c o n s t r i c t i o n ? Yes A n a l g e s i a Y e s ( ? ) Yes 145 from T a b l e 1 t h a t a degree of commonality does e x i s t between the symptoms of motion s i c k n e s s and those of morphine admin i s t r a t i o n . A l t h o u g h the e v i d e n c e i s somewhat c i c u m s t a n t i a l , the r e s e a r c h d e s c r i b e d above seems t o p o i n t t o a p o s s i b l e r o l e f o r o p i a t e s i n the n e u r a l m e d i a t i o n of motion s i c k n e s s . I f t h i s h y p o t h e s i s i s c o r r e c t , then drugs which are e f f e c t i v e i n p r e v e n t i n g or t r e a t i n g the nausea, v o m i t i n g , and o t h e r symptoms ind u c e d by o p i a t e t r e a t m e n t s h o u l d be e f f e c t i v e i n b l o c k i n g the motion s i c k n e s s syndrome. Two such drugs are naloxone and n a l t r e x o n e . These o p i a t e a n t a g o n i s t drugs have l i t t l e or no a g o n i s t a c t i v i t y , and a r e h i g h l y e f f e c t i v e i n r e v e r s i n g a l l of the e f f e c t s of morphine i n c l u d i n g nausea and v o m i t i n g ( J a f f e r & M a r t i n , 1975; Snyder & M a t t h y s s e , 1975). They w i l l a l s o r e v e r s e the n a u s e a t i n g and emetic a c t i o n s of apomorphine, a dopamine a g o n i s t t h a t i s thought t o e x e r t i t s emetic a c t i o n s by way of an o p i a t e r e c e p t o r mechanism w h i l e h a v i n g l i t t l e a n a l g e s i c a c t i o n . Naloxone w i l l a l s o b l o c k and r e v e r s e the emetic a c t i o n s of v e r y s m a l l q u a n t i t i e s of morphine a d m i n i s t e r e d i n t r a v e n t r i c u l a r l y i n the c a t ( S t e w a r t , W i e s b r o d t , & B u r k s , 1976). Naloxone, t h e n , may have some p o t e n t i a l as a t r e a t m e n t f o r motion s i c k n e s s . In a d d i t i o n t o the advantages of d i r e c t l y a n t a g o n i z i n g the mechanisms r e s p o n s i b l e f o r motion s i c k n e s s , naloxone would appear t o have o t h e r p o t e n t i a l advantages i n a t h e r a p e u t i c r o l e . N aloxone, u n l i k e c u r r e n t motion s i c k n e s s d r u g s , which produce d r o w s i n e s s , dry. mouth, and a v a r i e t y of o t h e r s i d e e f f e c t s (Reason & Brand, 1975; Wood, 1979), has few no major s i d e e f f e c t s when a d m i n i s t e r e d t o normal s u b j e c t s i n doses which w i l l 146 c o m p l e t e l y a n t a g o n i z e the e f f e c t s of morphine ( G r e v e r t & G o l d s t e i n , 1978). The purpose of Experiment 13 t h e n , was t o t e s t the h y p o t h e s i s t h a t motion s i c k n e s s i s mediated by an endogenous o p i a t e mechanism a c t i v a t e d by abnormal v e s t i b u l a r s t i m u l a t i o n . S u b j e c t s i n the p r e s e n t experiment were p r e - t r e a t e d w i t h the o p i a t e a n t a g o n i s t naloxone i n the e x p e c t a t i o n t h a t i f endogenous o p i a t e mechanisms were i n v o l v e d , naloxone would b l o c k the development of motion s i c k n e s s i n a n i m a l s so t r e a t e d . One d i f f i c u l t y i n the study of motion s i c k n e s s i n the r a t i s the f a c t t h a t r a t s appear t o be i n c a p a b l e of emesis ( C o i l & G a r c i a , 1977; Hatcher & W e i s s , 1923), the most commonly a c c e p t e d i n d i c a t o r of motion s i c k n e s s ( c f . B r i z z e e , Ordy, & M e h l e r , 1980; Money, 1970; S u r i , Crampton, & Daunton, 1979). I t i s c l e a r however, t h a t r a t s a r e e x t r e m e l y s e n s i t i v e t o v e s t i b u l a r s t i m u l a t i o n (Weismann & G o t t l i e b , 1969) and a v a r i e t y of i n d i c a t o r s have been proposed t o a s s a y motion s i c k n e s s i n t h e r a t . These i n d i c a t o r s i n c l u d e : l a t e n c y t o d r i n k i m m e d i a t e l y a f t e r exposure t o motion ( H a r o u t u n i a n , R i c c i o , & Gans, 1976), s u p p r e s s i o n of operant r e s p o n d i n g i n a r o t a t i n g environment ( R i c c i o & Thach, 1968), changes i n locomotor a c t i v i t y i n a r o t a t i n g environment, the f o r m a t i o n of c o n d i t i o n e d t a s t e a v e r s i o n s as a f u n c t i o n of exposure t o abnormal motion (Green & R a c h l i n , 1973, 1976), and the i n g e s t i o n of n o n - n u t r i t i v e s u b s t a n c e s f o l l o w i n g p e r i o d s of abnormal motion ( M i t c h e l l , Krusemark, & H a f n e r , 1977). Of t h e s e i n d i c a t o r s , o n l y two would appear t o be f r e e from p o s s i b l e c o n f o u n d i n g n o n - s p e c i f i c e f f e c t s of v e s t i b u l a r 147 s t i m u l a t i o n . I t i s d i f f i c u l t t o u n d e r s t a n d how m o t i o n - i n d u c e d i l l n e s s c o u l d be the o n l y f a c t o r p r o d u c i n g a s u p p r e s s i o n of m o t o r - a c t i v i t y , operant response r a t e , or speed w i t h which a an i m a l w i l l d r i n k . The f o r m a t i o n of a c o n d i t i o n e d t a s t e a v e r s i o n f o l l o w i n g motion and the consumption of n o n - n u t r i t i v e s u b s t a n c e s f o l l o w i n g r o t a t i o n on the o t h e r hand, would seem t o be much more a p p r o p r i a t e b e h a v i o u r a l a s s a y s f o r motion s i c k n e s s i n the r a t . C o n d i t i o n e d t a s t e a v e r s i o n r e f e r s t o the f i n d i n g t h a t an a n i m a l t h a t has been p o i s o n e d or o t h e r w i s e made i l l f o l l o w i n g exposure t o a n o v e l t a s t e w i l l s u b s e q u e n t l y a v o i d t h a t t a s t e ( G a r c i a , 1975; Gustavson, 1975). C o n d i t i o n e d ' p i c a ' , the consumption of n o n - n u t r i t i v e s u b s t a n c e s such as c l a y or d i r t , r e f e r s t o the r e c e n t f i n d i n g t h a t r a t s w i l l d r a m a t i c a l l y i n c r e a s e t h e i r i n t a k e of a c l a y or d i r t m i x t u r e f o l l o w i n g e i t h e r p o i s o n i n g ( M i t c h e l l , W i n t e r , & M o r i s a k i , 1 9 7 7 ) or a p e r i o d of abnormal motion ( M i t c h e l l , Krusemark, & Ha f n e r , 1977). I t has been argued t h a t some form of i l l n e s s or g a s t r i c d i s t u r b a n c e i s n e c c e s a r y f o r the development of both c o n d i t i o n e d t a s t e a v e r s i o n s ( C o i l & G a r c i a , 1977) and c o n d i t i o n e d p i c a ( M i t c h e l l , Krusemark, & H a f n e r , 1977; M i t c h e l l , L aycock, & Stephens, 1977). I f g a s t r o - i n t e s t i n a l d i s t u r b a n c e i s n e c e s s a r y f o r t h e s e e f f e c t s , i t s u g g e s t s t h a t motion i s somehow p r o d u c i n g g a s t r i c d i s t u r b a n c e s i n the r a t t h a t a r e analogo u s t o motion s i c k n e s s i n o t h e r s p e c i e s . Of these two t e c h n i q u e s , the c o n d i t i o n e d t a s t e a v e r s i o n would perhaps be the most i n s e n s i t i v e t o c o n f o u n d i n g n o n - s p e c i f i c e f f e c t s as the s t r e n g t h of the t a s t e a v e r s i o n can be t e s t e d w e l l a f t e r the p a i r i n g of the n o v e l f l a v o u r and abnormal m o t i o n . Thus, the t a s t e a v e r s i o n was chosen here t o 148 t e s t the p o s s i b l e b l o c k i n g e f f e c t s of an o p i a t e a n t a g o n i s t , n a l o x o n e , on the f o r m a t i o n of a m o t i o n - i n d u c e d c o n d i t i o n e d t a s t e a v e r s i o n i n r a t s . METHOD S u b j e c t s The s u b j e c t s were 24 male b l a c k hooded r a t s w e i g h i n g a p p r o x i m a t e l y 375 gm t h a t had s e r v e d i n the r e s t r a i n t c o n d i t i o n of Experiment 5. A l l s u b j e c t s were i n d i v i d u a l l y housed i n s t a n d a r d hanging cages as p r e v i o u s l y d e s c r i b e d and food was f r e e l y a v a i l a b l e throughout the e x p e r i m e n t . P r o c e d u r e The p r e s e n t experiment c o n s i s t e d of two phases: a 6 day b a s e l i n e phase i n which each s u b j e c t ' s p r e f e r e n c e f o r a n o v e l s a c c h a r i n d r i n k i n g s o l u t i o n was a s s e s s e d , f o l l o w e d by a t e s t i n g phase i n which the e f f e c t s of naloxone and abnormal motion on s a c c h a r i n p r e f e r e n c e were a s s e s s e d . B a s e l i n e phase. On each of the 6 days of the b a s e l i n e phase of the e x p e r i m e n t , each r a t was a l l o w e d 10 min a c c e s s t o b o t h t a p water and a .1% (w/v) sodium s a c c h a r i n d r i n k i n g s o l u t i o n . The s o l u t i o n s were p r e s e n t e d i n two s i d e - b y - s i d e g r a d u a t e d d r i n k i n g tubes a t t a c h e d t o the the f r o n t of each cage. The p o s i t i o n s of the t a p water and s a c c h a r i n s o l u t i o n s were r e v e r s e d each day t o a v o i d p o s s i b l e p o s i t i o n p r e f e r e n c e s . Immediately p r i o r t o the 10 min d r i n k i n g p e r i o d , each r a t was i n j e c t e d ( i . p . ) w i t h a s t e r i l e s a l i n e s o l u t i o n (.9% w/v, 1 m l / k g ) . The purpose of the s a l i n e i n j e c t i o n was t o accustom the r a t s t o the i n j e c t i o n p r o c e d u r e and hence t o a t t e n u a t e any d i s r u p t i v e e f f e c t s of the i n j e c t i o n p rocedure i n the t e s t phase 149 of the e x p e r i m e n t . F o l l o w i n g the 10 min d r i n k i n g p e r i o d , the volumes of each s o l u t i o n consumed were r e c o r d e d and a p e r c e n t a g e s a c c h a r i n p r e f e r e n c e s c o r e c a l c u l a t e d based on the t o t a l f l u i d c onsumption. No o t h e r d r i n k i n g f l u i d was a v a i l a b l e a t any time throughout the c o u r s e of the e x p e r i m e n t . Test phase. On the s i x t h day, 12 of the a n i m a l s r e c e i v e d naloxone i n j e c t i o n s (1.0 mg/kg) i n l i e u of the p r e v i o u s s a l i n e i n j e c t i o n s . Naloxone h y d r o c h l o r i d e (Endo) was d i s s o l v e d i n s t e r i l e s a l i n e a t a c o n c e n t r a t i o n of 1 mg/ml, thus e n s u r i n g t h a t the i n j e c t i o n volume was e q u i v a l e n t t o the p r e v i o u s s a l i n e i n j e c t i o n s . The r e m a i n i n g 12 a n i m a l s r e c e i v e d s a l i n e i n j e c t i o n s . A f t e r the 10-min d r i n k i n g p e r i o d , s i x a n i m a l s from each of the s a l i n e (SAL) and naloxone (NAL) i n j e c t e d groups were randomly a s s i g n e d t o e i t h e r the motion (MOT) or r e s t r a i n t c o n d i t i o n (REST). The d e s i g n was thus a 2 X 2 f a c t o r i a l d e s i g n w i t h motion v e r s u s r e s t r a i n t and s a l i n e v e r s u s naloxone as the two l e v e l s of each f a c t o r . The abnormal motion c o n s i s t e d of h o r i z o n t a l r o t a t i o n (30 RPM) i n c o m b i n a t i o n w i t h v e r t i c a l o s c i l l a t i o n (50 c y c l e s / m i n ) f o r a p e r i o d of 15 min. T h i s motion was i d e n t i c a l t o t h a t d e s c r i b e d i n p r e v i o u s e x p e r i m e n t s and was s i m i l a r t o t h a t d e s c r i b e d by B r i z z e e and co-workers ( B r i z z e e , Ordy, & M e h l e r , 1980; Ordy & B r i z z e e , 1980) i n t h e i r s t u d i e s of m o t i o n - i n d u c e d food a v e r s i o n s i n the s q u i r r e l monkey. As the d e v i c e used t o a d m i n i s t e r the motion was c a p a b l e of h o l d i n g s i x r a t s s i m u l t a n e o u s l y , the experiment was conducted i n two squads of 12 a n i m a l s each. Each squad c o n t a i n e d t h r e e r a t s from each of the 4 groups. The r e s t r a i n t c o n d i t i o n i n v o l v e d p l a c i n g the 150 r a t s i n the r e s t r a i n i n g tubes and p l a c i n g the s i x tubes i n a w i r e mesh c a r r i e r s i m i l a r t o t h a t used i n the motion d e v i c e . The c a r r i e r was then merely p l a c e d on a t a b l e a d j a c e n t t o the motion d e v i c e f o r the 15 min d u r a t i o n of the motion c o n d i t i o n . The e n t i r e p r o c e d u r e of Day 6 was r e p e a t e d on t e s t Days 7 and 8. S a c c h a r i n p r e f e r e n c e s c o r e s f o r Day 7 and 8 th e n , r e f l e c t the e f f e c t of the motion and drug t r e a t m e n t s of the p r e c e d i n g day of t e s t i n g . Day 7 p r e f e r e n c e s c o r e s f o r example, r e p r e s e n t the e f f e c t of p a i r i n g s a c c h a r i n and motion on Day 6; whereas Day 8 p r e f e r e n c e s c o r e s r e p r e s e n t the e f f e c t of p a i r i n g s a c c h a r i n and motion on Day 7. RESULTS For each r a t , a mean p r e f e r e n c e s c o r e f o r b a s e l i n e days 5 and 6 combined and a mean p r e f e r e n c e s c o r e f o r t e s t days 7 and 8 were c a l c u l a t e d t o a l l o w comparison of the p r e - and p o s t -t r e a t m e n t p r e f e r e n c e s c o r e s . Group means f o r t h e s e p r e - and p o s t - t r e a t m e n t s c o r e s a r e shown i n F i g u r e 21. I t i s apparent from F i g u r e 21 t h a t exposure t o abnormal motion appears t o r e s u l t i n a s u b s t a n t i a l a t t e n u a t i o n of the r a t s ' p r e f e r e n c e f o r a p r e v i o u s l y p r e f e r r e d s u b s t a n c e : a c o n d i t i o n e d t a s t e a v e r s i o n . F u r t h e r d a t a r e d u c t i o n was a c c o m p l i s h e d by c a l c u l a t i n g d i f f e r e n c e s c o r e s between p r e - and p o s t - t r e a t m e n t p r e f e r e n c e s c o r e s f o r each a n i m a l . These d i f f e r e n c e s c o r e s were then s u b j e c t e d t o a c o n s t a n t a d d i t i o n t r a n s f o r m t o a l l o w f u r t h e r a n a l y s i s . A n a l y s i s of v a r i a n c e on the t r a n s f o r m e d d i f f e r e n c e s c o r e s i n d i c a t e d o n l y a s i g n i f i c a n t e f f e c t of motion (F=7.35, d f = l / 2 0 , p<.05) on s a c c h a r i n p r e f e r e n c e , thus c o n f i r m i n g t h a t abnormal motion i s c a p a b l e of 151 FIGURE 21. Mean s a c c h a r i n p r e f e r e n c e b e f o r e (PRE-UCS) and a f t e r (POST) p a i r i n g of s a c c h a r i n and motion (MOT) or r e s t r a i n t (REST) i n r a t s t h a t had been t r e a t e d w i t h naloxone h y d r o c h l o r i d e (NAL) or s a l i n e (SAL) i n Experiment 15. 152 90 5 80 LU O 70 2 LU Lu 60 LL LU DC CL 50 40 DC < X o £ 30 < 20 LU 10 j j PRE-UCS • POST T" SAL NAL SAL NAL REST REST MOT MOT 153 p r o d u c i n g a c o n d i t i o n e d t a s t e a v e r s i o n i n r a t s . Naloxone however, had no s i g n i f i c a n t e f f e c t (F=.47, d f = l / 2 0 , p>.05) on the f o r m a t i o n of a c o n d i t i o n e d t a s t e a v e r s i o n t o abnormal moti o n . There was a l s o no s i g n i f i c a n t i n t e r a c t i o n (F=.12, d f = l / 2 0 , p>.05). DISCUSSION Naloxone h y d r o c h l o r i d e , at l e a s t a t the dose used he r e , f a i l e d t o b l o c k the t a s t e a v e r s i o n produced by abnormal mot i o n . In a d d i t i o n , the t r e n d i n d i c a t e d i n F i g u r e 21, a l t h o u g h not s t a t i s t i c a l l y s i g n i f i c a n t , would suggest t h a t naloxone may have an a v e r s i v e component of i t s own t h a t i s d e t e c t a b l e i n the t a s t e a v e r s i o n paradigm. P o s s i b l e e x p l a n a t i o n s f o r the f a i l u r e of naloxone t o b l o c k the development of a c o n d i t i o n e d t a s t e a v e r s i o n a r e many and v a r i e d . The most l i k e l y e x p l a n a t i o n i s t h a t the h y p o t h e s i s i s i n c o r r e c t . A l t h o u g h t h i s may be t r u e , i t s h o u l d be noted t h a t one t e s t of the h y p o t h e s i s a t one dose l e v e l does not c o n s t i t u t e an adequate t e s t of the h y p o t h e s i s . The dose l e v e l chosen may not have produced s u f f i c i e n t r e c e p t o r b l o c k i n g t o b l o c k the appearance of the c o n d i t i o n e d t a s t e a v e r s i o n . L e B l a n c and C a p p e l l (1975), and van der Kooy and P h i l l i p s (1977), u s i n g morphine as an u n c o n d i t i o n e d s t i m u l u s (UCS) r a t h e r than abnormal motio n , have shown t h a t the dose of naloxone adequate t o b l o c k a t a s t e a v e r s i o n t o a g i v e n dose of morphine l i e s w i t h i n a v e r y narrow range. Above and below t h i s dosage, the t a s t e a v e r s i o n appears q u i t e s t r o n g and i s thought t o r e p r e s e n t the e f f e c t s of morphine and an e f f e c t of exc e s s n a l o x o n e . However, a t t e m p t s i n our l a b o r a t o r y t o b l o c k 154 c o n d i t i o n e d t a s t e a v e r s i o n s r e s u l t i n g from abnormal motion w i t h a v a r i e t y of naloxone doses (.0125 t o 7.5 mg/kg) have been u n s u c c e s s f u l ( u n p u b l i s h e d d a t a ) . The a v e r s i v e n a t u r e of naloxone i n the t a s t e a v e r s i o n paradigm has a l s o been noted by o t h e r a u t h o r s . P i l c h e r , S t o l e r m a n , and D'Mello, (1978) f o r example, have noted t h a t naloxone i s an e f f e c t i v e s t i m u l u s f o r i n d u c i n g c o n d i t i o n e d t a s t e a v e r s i o n s i n r a t s and S t o l e r m a n , P i l c h e r , and D'Mello(1978) have c o n f i r m e d t h i s e f f e c t at doses as low as 1.0 mg/kg. These a u t h o r s have a l s o demonstrated t h a t t h i s t a s t e a v e r s i o n i n d u c i n g p r o p e r t y i s s t e r e o s p e c i f i c , s u g g e s t i n g a d i r e c t a c t i o n on a p a r t i c u l a r b i n d i n g s i t e (Snyder & P e r t , 1975). Another p o s s i b l e e x p l a n a t i o n f o r the f a i l u r e of naloxone t o b l o c k the c o n d i t i o n e d t a s t e a v e r s i o n i s somewhat more s p e c u l a t i v e , and r e l i e s on the pharmacodynamics of naloxone i n r a t s ( N g a i , B e r k o w i t z , Yang, Hempstead, & S p e c t o r , 1976). I t i s p o s s i b l e t h a t the naloxone t r e a t m e n t may produce s u p e r s e n s i t i v i t y of the o p i a t e r e c e p t o r upon r e c o v e r y from n a l o x o n e . T h i s s u p e r s e n s i t i v i t y does appear t o e x i s t f o r a t l e a s t c h r o n i c naloxone t r e a t m e n t ( S c h u l z , W u r s t e r , & Herz, 1979). I f the o p i a t e r e c e p t o r i s s u p e r s e n s i t i v e f o l l o w i n g naloxone t r e a t m e n t , then the r e t u r n of endogenous o p i a t e s t o the r e c e p t o r s p r e v i o u s l y o c c u p i e d by naloxone may produce an e f f e c t s i m i l a r t o t h a t of the o p i a t e system a c t i v a t i o n by abnormal m o t i o n , and t h u s e f f e c t i v e l y produce a t a s t e a v e r s i o n . Naloxone has a v e r y s h o r t d u r a t i o n of a c t i o n i n r a t s and t h i s e f f e c t c o u l d o c c u r r e l a t i v e l y c l o s e i n time t o the e f f e c t s of abnormal motion i n the s a l i n e - i n j e c t e d a n i m a l s . Given the wide range of 155 d e l a y s between the c o n d i t i o n e d s t i m u l u s ( f l a v o r ) and the UCS t h a t w i l l s t i l l produce a c o n d i t i o n e d t a s t e a v e r s i o n ( G a r c i a & Hankins 1975; Gustavson, 1975), the time d i f f e r e n c e between the motion UCS and the naloxone w i t h d r a w a l UCS may not be d e t e c t a b l e i n a p r e f e r e n c e t e s t 24 hr l a t e r . These two d i f f i c u l t i e s , the s h o r t d u r a t i o n of a c t i o n and the t a s t e a v e r s i o n i n d u c i n g p r o p e r t i e s of n a l o x o n e , prompted a f u r t h e r s t u d y of p o s s i b l e endogenous o p i a t e i n v o l v e m e n t i n motion s i c k n e s s u s i n g a d i f f e r e n t o p i a t e a n t a g o n i s t , n a l t r e x o n e . Experiment 14 Experiment 14, l i k e Experiment 13, e x p l o r e d the p o s s i b l e a t t e n u a t i n g e f f e c t s of an o p i a t e a n t a g o n i s t on c o n d i t i o n e d t a s t e a v e r s i o n s produced by exposure t o abnormal motion i n r a t s . Because n a l t r e x o n e has a l o n g e r d u r a t i o n of a c t i o n than does naloxone ( J a f f e & M a r t i n , 1975) and a l s o appears t o have fewer a v e r s i v e p r o p e r t i e s of i t s own compared t o naloxone i n the c o n d i t i o n e d t a s t e a v e r s i o n paradigm ( S t o l e r m a n , P i l c h e r , & D 'Mello, 1978), n a l t r e x o n e was the o p i a t e a n t a g o n i s t employed i n the p r e s e n t e x p e r i m e n t . The dose of n a l t r e x o n e chosen (3.0 mg/kg) was one t h a t has been p r e v i o u s l y shown t o e f f e c t i v e l y b l o c k o p i a t e r e c e p t o r mechanisms w h i l e h a v i n g l i t t l e e f f e c t i v e n e s s i n p r o d u c i n g t a s t e a v e r s i o n s ( S t o l e r m a n et a l . , 1978). I t i s a l s o p o s s i b l e t h a t r e p e a t e d a d m i n i s t r a t i o n of naloxone and abnormal motion was a c o n f o u n d i n g f a c t o r i n the p r e v i o u s e x p e r i m e n t . In the p r e s e n t e x p e r i m e n t , th e t a s t e a v e r s i o n paradigm was m o d i f i e d t o a s i n g l e f o r c e d exposure t r i a l f o l l o w e d one day l a t e r by a s i n g l e two b o t t l e p r e f e r e n c e t e s t . 156 METHOD S u b j e c t s S e r v i n g as s u b j e c t s i n the p r e s e n t experiment were 60 n a i v e male hooded r a t s , w e i g h i n g a p p r o x i m a t e l y 300 gm. The a n i m a l s were purchased as p r e v i o u s l y d e s c r i b e d and were housed i n d i v i d u a l l y i n hanging w i r e cages f o r a p e r i o d of 14 days p r i o r t o the s t a r t of the e x p e r i m e n t . P r o c e d u r e The e n t i r e experiment was c a r r i e d out over a 3-day p e r i o d . On Day 1, water b o t t l e s were removed from the cages and no f u r t h e r f l u i d was a v a i l a b l e u n t i l the s a c c h a r i n exposure t r i a l on Day 2. Twenty-four hr f o l l o w i n g removal of the water b o t t l e s , 30 a n i m a l s were i n j e c t e d w i t h n a l t r e x o n e h y d r o c h l o r i d e (3.0 mg/kg, i . p . ) , and the r e m a i n i n g 30 a n i m a l s were i n j e c t e d w i t h the s a l i n e v e h i c l e . N a l t r e x o n e h y d r o c h l o r i d e was d i s s o l v e d i n s t e r i l e s a l i n e (3.0 mg/ml) and v e h i c l e i n j e c t i o n s were equivolume i n j e c t i o n s of s t e r i l e s a l i n e . Immediately f o l l o w i n g the drug i n j e c t i o n s , a sodium s a c c h a r i n s o l u t i o n (.1% w/v) was p r e s e n t e d t o each r a t f o r a 15 min p e r i o d . The volume of s o l u t i o n consumed i n the 15 min p e r i o d was r e c o r d e d t o the n e a r e s t ml. W i t h i n 5 min f o l l o w i n g the s a c c h a r i n exposure t r i a l , 15 a n i m a l s from each of the n a l t r e x o n e and s a l i n e i n j e c t i o n groups were p l a c e d i n the r e s t r a i n i n g tubes and s u b j e c t e d t o the h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n s t i m u l u s used i n Experiment 13 f o r a 15-min p e r i o d . The r e m a i n i n g 15 a n i m a l s from each of the n a l t r e x o n e and s a l i n e groups underwent a 15-min p e r i o d of r e s t r a i n t , i n a manner i d e n t i c a l t o t h a t p r e v i o u s l y d e s c r i b e d . The e x p e r i m e n t a l d e s i g n 157 was thus a 2 X 2 f a c t o r i a l d e s i g n w i t h n a l t r e x o n e or s a l i n e and motion or r e s t r a i n t as the l e v e l s of the two f a c t o r s . As the d e v i c e used t o a d m i n i s t e r the motion had a s i x r a t c a p a c i t y , r a t s were run i n squads of 12 a n i m a l s each, composed of t h r e e r a t s from each of the f o u r c o n d i t i o n s . On Day 3, 24 hr a f t e r the motion or r e s t r a i n t t r e a t m e n t , a two c h o i c e p r e f e r e n c e t e s t was conducted. Two d r i n k i n g t u b e s , one c o n t a i n i n g sodium s a c c h a r i n s o l u t i o n (.1% w/v) and the o t h e r t a p w a t e r , were a t t a c h e d t o the f r o n t of the cage and the r a t s a l l o w e d t o d r i n k f o r a 15 min p e r i o d . F o l l o w i n g the 15 min t e s t p e r i o d , the volume of each f l u i d consumed was r e c o r d e d and the p e r c e n t a g e of s a c c h a r i n s o l u t i o n consumed r e l a t i v e t o the t o t a l volume consumed was c a l c u l a t e d . Rats t h a t drank no s a c c h a r i n s o l u t i o n on e i t h e r Day 2 or 3 were d e l e t e d from f u r t h e r a n a l y s i s and the number of a n i m a l s per group was reduced a c c o r d i n g l y . RESULTS As Shown i n F i g u r e 22, exposure t o abnormal motion r e s u l t e d i n a d r a m a t i c decrease i n subsequent s a c c h a r i n p r e f e r e n c e f o l l o w i n g a s i n g l e exposure t o s a c c h a r i n p r i o r t o abnormal m o t i o n . As i n Experiment 13, a d m i n i s t r a t i o n of an o p i a t e a n t a g o n i s t p r i o r t o the a d m i n i s t r a t i o n of abnormal motion had l i t t l e e f f e c t on subsequent s a c c h a r i n p r e f e r e n c e save f o r a s l i g h t t r e n d towards i n c r e a s e d a v o i d a n c e of the s o l u t i o n . A n a l y s i s of v a r i a n c e c o n f i r m e d t h e presence of a c o n d i t i o n e d t a s t e a v e r s i o n i n the abnormal motion groups (F=6.06, d f = l / 4 4 , p<.05). There was no s i g n i f i c a n t e f f e c t of n a l t r e x o n e (F=.32, d f = l / 4 4 , p>.05) nor was the i n t e r a c t i o n between n a l t r e x o n e and abnormal motion s i g n i f i c a n t (F=.58, d f = l / 4 4 , p>.05). 158 FIGURE 22. Mean s a c c h a r i n p r e f e r e n c e a f t e r p a i r i n g of s a c c h a r i n p r e s e n t a t i o n and motion (MOT) or r e s t r a i n t (REST) i n r a t s t h a t had been p r e - t r e a t e d w i t h n a l t r e x o n e (NAL) o r s a l i n e (SAL) i n Experiment 14. Numbers w i t h i n the b a r s r e f e r t o the number of a n i m a l s per group. LU o UJ DC LU LL LU DC D_ DC < O o < CO < LU 80 70 60 50 40 30 20 10 11 14 S A L REST SAL MOT NAL REST NAL MOT 160 DISCUSSION I t would appear from the r e s u l t s of the p r e s e n t experiment and the p r e c e d i n g experiment t h a t t h e r e i s no s i m p l e or o b v i o u s r e l a t i o n s h i p between o p i a t e a n t a g o n i s t s and the mechanisms of motion s i c k n e s s . N e i t h e r naloxone nor n a l t r e x o n e , two r e l a t i v e l y pure o p i a t e a n t a g o n i s t d r u g s , appeared t o p r e v e n t the development of a c o n d i t i o n e d a v e r s i o n t o a n o v e l f l a v o r when abnormal motion was used as the p r o v o c a t i v e s t i m u l u s . A l t h o u g h the most p a r s i m o n i o u s e x p l a n a t i o n f o r the r e s u l t s of t h e s e two e x p e r i m e n t s i s t h a t the h y p o t h e s i s i s i n c o r r e c t , t h e r e a r e a number of a l t e r n a t e hypotheses t h a t may a l s o e x p l a i n the f a i l u r e of o p i a t e a n t a g o n i s t s t o b l o c k the development of the c o n d i t i o n e d t a s t e a v e r s i o n . F i r s t , i t appears t h a t t h e r e a r e a number of d i f f e r e n t o p i a t e r e c e p t o r s i n the c e n t r a l nervous system t h a t a r e d i f f e r e n t i a l l y s e n s i t i v e t o o p i a t e a n t a g o n i s t drugs (Cheng & Pomeranz, 1980; L o r d , W a t e r f i e l d , Hughes, & K o s t e r l i t z , 1976; Ward, M e t c a l f , & Rees, 1978). I f the o p i a t e r e c e p t o r mechanism t h a t p o t e n t i a l l y mediates m o t i o n - i n d u c e d t a s t e a v e r s i o n s i s i n s e n s i t i v e t o b l o c k a d e w i t h o p i a t e a n t a g o n i s t d r u g s , one would not e xpect o p i a t e a n t a g o n i s t drugs t o b l o c k the i l l n e s s - i n d u c i n g p r o p e r i e s of abnormal m o t i o n . The e x i s t e n c e of the d i f f e r e n t i a l l y s p e c i f i c sub-p o p u l a t i o n s of o p i a t e r e c e p t o r s i s not o n l y f e a s i b l e , but many a u t h o r s have suggested (see A d l e r , 1980; Cheng & Pomeranz, 1980, G o l d s t e i n , 1978) t h a t t h e many d i f f e r e n t b e h a v i o u r a l e f f e c t s of o p i a t e s c o u l d be i n d i v i d u a l l y m e d i a t e d by d i f f e r e n t r e c e p t o r p o p u l a t i o n s . 161 I t i s a l s o p o s s i b l e t h e n , t h a t the o p i a t e r e c e p t o r mechanism r e s p o n s i b l e f o r m e d i a t i n g m o t i o n - i n d u c e d t a s t e a v e r s i o n i s l e s s s p e c i f i c f o r o p i a t e a n t a g o n i s t s than f o r the endogenous l i g a n d . I f t h i s were t r u e , i t i s p o s s i b l e t h a t the endogenous p e p t i d e s r e l e a s e d by abnormal motion c o u l d d i s p l a c e the naloxone m o l e c u l e from the r e c e p t o r s i t e and hence e x e r t t h e i r normal o p i a t e - l i k e e f f e c t s . A second h y p o t h e s i s i n v o l v e s the d i f f i c u l t y i n e s t a b l i s h i n g the a p p r o p r i a t e dosage r e l a t i o n s h i p of the o p i a t e a n t a g o n i s t t o the endogenous o p i a t e p e p t i d e . As mentioned p r e v i o u s l y , naloxone w i l l b l o c k the t a s t e a v e r s i o n i n d u c i n g p r o p e r t i e s of morphine a d m i n i s t r a t i o n but o n l y a t c e r t a i n morphine-naloxone dosage c o m b i n a t i o n s (LeBlanc & C a p p e l l , 1975; van der Kooy & P h i l l i p s , 1977). A s i m i l a r s i t u a t i o n may have e x i s t e d i n the p r e s e n t e x p e r i m e n t s such t h a t the dose of a n t a g o n i s t used may have been i n a p p r o p r i a t e f o r the degree of endogenous o p i a t e i n v o l v e m e n t . A t h i r d e x p l a n a t i o n r e s t s on the a p p r o p r i a t e n e s s of the c o n d i t i o n e d t a s t e a v e r s i o n paradigm as an index of motion s i c k n e s s i n the r a t . I t may be t h a t the development of a c o n d i t i o n e d t a s t e a v e r s i o n i s not analogous t o the motion s i c k n e s s phenomenon. I t appears t h a t t h e r e a r e a wide v a r i e t y of n e u r a l p r o c e s s e s i n v o l v e d i n c o n d i t i o n e d t a s t e a v e r s i o n ( C o i l & G a r c i a , 1977) and a v a r i e t y of hypotheses c o n c e r n i n g the development of t a s t e a v e r s i o n s (e.g. Braveman, 1975; Gamzu, 1975). To d a t e , the o n l y r e l i a b l e e v i d e n c e s u g g e s t i n g t h a t motion s i c k n e s s and c o n d i t i o n e d t a s t e a v e r s i o n may be analogous i s the f a c t t h a t 162 b o th may be induced by exposure t o abnormal m o t i o n . T h i s commonality does n o t , of c o u r s e , imply t h a t b oth phenomena are n e c e s s a r i l y s u bserved by i d e n t i c a l u n d e r l y i n g mechanisms. Hence, i n a t t e m p t i n g t o i n v e s t i g a t e the u n d e r l y i n g mechanisms of motion s i c k n e s s t h rough a c o n d i t i o n e d t a s t e a v e r s i o n , one may i n f a c t be s t u d y i n g o n l y the mechanisms of the t a s t e a v e r s i o n . T h i s p o i n t i s o f f e r e d here o n l y as a p o s s i b l e e x p l a n a t i o n f o r the r e s u l t s of E x p e r i m e n t s 13 and 14 but i s c o n s i d e r e d i n g r e a t e r d e t a i l i n a subsequent d i s c u s s i o n . A l t h o u g h a d m i n i s t r a t i o n of o p i a t e a n t a g o n i s t s d i d not b l o c k the f o r m a t i o n of a c o n d i t i o n e d t a s t e a v e r s i o n f o l l o w i n g exposure t o abnormal motio n , the f a c t remains t h a t a s t r o n g t a s t e a v e r s i o n was produced by the m o t i o n . I f endogenous o p i a t e s a r e not i n v o l v e d i n m e d i a t i n g the cue p r o p e r t i e s of the a v e r s i v e s t i m u l u s , then what s o r t of system may be i n v o l v e d ? One p o s s i b l e e x p l a n a t i o n f o r the f o r m a t i o n of the t a s t e a v e r s i o n has been proposed by Braveman (1975). T h i s h y p o t h e s i s s u g gests t h a t the u n c o n d i t i o n e d s t i m u l u s a c t s as a ' s t r e s s o r ' and i t i s the a c t i v a t i o n of the p i t u i t a r y - a d r e n a l system by t h i s s t r e s s o r t h a t m e d i ates the i l l n e s s - c u e p r o p e r t i e s of the s t i m u l u s . The f a c t t h a t exposure t o one of a v a r i e t y of s t r e s s o r s w i l l b l o c k the e f f e c t i v e n e s s of a n other u n c o n d i t i o n e d s t i m u l u s i n p r o d u c i n g a t a s t e a v e r s i o n , and the f a c t t h a t exposure t o t h e s e s t i m u l i i s accompanied by i n c r e a s e d c o r t i c o s t e r o i d l e v e l s (Braveman, 1975) s u g g e s t s t h a t t h e s e d i f f e r e n t s t i m u l i may a c t t h r o u g h a common mechanism, the p i t u i t a r y - a d r e n a l system. Recent e v i d e n c e d e m o n s t r a t i n g t h a t dexamethasone w i l l a t t e n u a t e t a s t e a v e r s i o n s and t h a t ACTH w i l l p r o l o n g e x t i n c t i o n of t a s t e a v e r s i o n s 163 (Hennesy, Smotherman, & L e v i n e , 1980) p r o v i d e s support f o r t h i s h y p o t h e s i s . I t i s p o s s i b l e t h a t a s i m i l a r s t r e s s e f f e c t was r e s p o n s i b l e f o r the t a s t e a v e r s i o n - i n d u c i n g p r o p e r t i e s of abnormal motion seen h e r e . As d i s c u s s e d p r e v i o u s l y , exposure t o abnormal motion produces p h y s i o l o g i c a l changes c o n s i s t e n t w i t h the proposed r o l e of abnormal motion as a s t r e s s o r . T h i s h y p o t h e s i s may a l s o e x p l a i n the s l i g h t f a c i l i t a t i n g e f f e c t of o p i a t e a n t a g o n i s t s i n E x p e r i m e n t s 13 and 14. E i s e n b e r g (1980) has r e c e n t l y demonstrated t h a t naloxone may a c t as a s t r e s s o r at l e a s t as measured by i n c r e a s e d c o r t i c o s t e r o n e l e v e l s as a r e s u l t of naloxone a d m i n i s t r a t i o n . A l t h o u g h the e n d o r p h i n h y p o t h e s i s of motion s i c k n e s s cannot be e l i m i n a t e d , n e i t h e r can i t be s u p p o r t e d . F o l l o w i n g the c o m p l e t i o n of Experiments 13 and 14, i t was d i s c o v e r e d t h a t t h i s h y p o t h e s i s has a l s o been i n d e p e n d e n t l y t e s t e d i n another l a b o r a t o r y . Money and h i s co-workers ( p e r s o n a l communication, 1980) have i n v e s t i g a t e d the e f f e c t s of o p i a t e a n t a g o n i s t s on mot i o n - i n d u c e d v o m i t i n g i n the dog. No change was found i n e i t h e r the l a t e n c y t o vomit or the c h a r a c t e r i s t i c s of the emetic r e s p o n s e . Exper iment 15 Experiment 15 attempted t o i n v e s t i g a t e the ' c a l m i n g ' or a n x i o l y t i c e f f e c t of abnormal m o t i o n . V e s t i b u l a r s t i m u l a t i o n has been found t o reduce c r y i n g time and o t h e r s i g n s of d i s t r e s s i n human i n f a n t s (Korner & Thoman, 1972; Pederson & Ter V r u g t , 1973; Weeks, 1979) and i s thought t o be more e f f e c t i v e i n s o o t h i n g i n f a n t s than are o t h e r common t e c h n i q u e s (Korner & 164 Thoman, 1972). Pederson and Ter V r u g t (1973) have found t h a t the c a l m i n g e f f e c t s of v e s t i b u l a r s t i m u l a t i o n can f a r o u t l a s t the d u r a t i o n of the s t i m u l u s i n human i n f a n t s and t h a t t h e r e i s an o p t i m a l f r e q u e n c y of v e r t i c a l r o c k i n g t h a t i s most e f f e c t i v e i n p r o d u c i n g t h i s e f f e c t . A l t h o u g h i t has been suggested t h a t t h i s r a t h e r p o o r l y d e f i n e d c a l m i n g e f f e c t i s due t o v e s t i b u l a r s t i m u l a t i o n , n o n - s p e c i f i c e f f e c t s of the s t i m u l u s such as a p p a r a t u s n o i s e , mere s t i m u l u s r e p e t i t i o n , e t c . , were c o n f o u n d i n g f a c t o r s i n the above-mentioned e x p e r i m e n t s . A s i d e from these few s t u d i e s i n human i n f a n t s , l i t t l e s y s t e m a t i c r e s e a r c h has been conducted c o n c e r n i n g the p o s s i b l e c a l m i n g e f f e c t s of v e s t i b u l a r s t i m u l a t i o n i n the a d u l t . " Drowsiness" and " l e t h a r g y " (Reason & Brand, 1975) have been noted as symptoms of motion s i c k n e s s and may r e f l e c t the same mechanism as the c a l m i n g e f f e c t s i n i n f a n t s a l t h o u g h n e i t h e r have been e x t e n s i v e l y s t u d i e d . Weeks (1979) p o i n t s out t h a t t h e r e e x i s t s much a n e c d o t a l e v i d e n c e c o n c e r n i n g the e f f i c a c y of r o c k i n g or s w i n g i n g movements i n i n d u c i n g r e l a x a t i o n and d r o w s i n e s s . T h i s p o s s i b l e c a l m i n g e f f e c t has a l s o not been e x t e n s i v e l y i n v e s t i g a t e d i n a n i m a l s . Thoman and Korner (1971) have demonstrated t h a t v e s t i b u l a r s t i m u l a t i o n i n i n f a n t r a t s reduces s i g n s of d i s t r e s s i n a manner s i m i l a r t o t h a t d e s c r i b e d f o r human i n f a n t s . However, t h i s s t u d y has been e x t e n s i v e l y c r i t i c i z e d on m e t h o d o l o g i c a l grounds (LaBarba & S t e w a r t , 1978). S t a u b l i and Huston (1979) i n a r e c e n t r e p o r t d e s c r i b i n g a new a v o i d a n c e t a s k , noted t h a t the a n i m a l s t e s t e d i n the paradigm were s u b j e c t e d t o a p e r i o d of s w i n g i n g p r i o r t o b e i n g p l a c e d on 165 a shock g r i d . T h i s b r i e f p e r i o d of s w i n g i n g was s a i d t o "calm" the a n i m a l s and f a c i l i t a t e placement on the g r i d . I t i s c l e a r from t h i s b r i e f d i s c u s s i o n t h a t l i t t l e r e s e a r c h e x i s t s c o n c e r n i n g the p u t a t i v e ' c a l m i n g ' e f f e c t s of v e s t i b u l a r s t i m u l a t i o n and t h a t which does e x i s t i s p o o r l y c o n t r o l l e d and d i f f i c u l t t o i n t e r p r e t . The purpose of the p r e s e n t experiment t h e n , was t o i n v e s t i g a t e the p o s s i b l e c a l m i n g e f f e c t s of abnormal v e s t i b u l a r s t i m u l a t i o n i n r a t s i n a w e l l - c o n t r o l l e d e x p e r i m e n t a l environment. A number of b e h a v i o u r a l a s s a y s have been proposed t o i n v e s t i g a t e ' c a l m i n g ' or a n x i o l y t i c e f f e c t s i n a n i m a l s ( G l i c k , 1976). These paradigms have been p r i m a r i l y used t o i n v e s t i g a t e the a n x i o l y t i c a c t i o n s of v a r i o u s p h a r m a c o l o g i c a l t r e a t m e n t s and almost a l l r e l y on o b s e r v i n g changes i n b e h a v i o u r when the a n i m a l i s exposed t o an a v e r s i v e or ' f e a r - p r o d u c i n g ' s t i m u l u s . A t t e n u a t i o n of the a n i m a l s normal response t o the a v e r s i v e s t i m u l u s by a drug or o t h e r t r e a t m e n t i s g e n e r a l l y assumed t o r e f l e c t a c a l m i n g or a n x i o l y t i c a c t i o n of t h a t t r e a t m e n t . P i n e l and T r e i t ( i n p r e s s , 1981) and T r e i t (1981) have r e c e n t l y d e s c r i b e d a r e l i a b l e and e a s i l y a d m i n i s t e r e d b e h a v i o u r a l assay f o r a n x i o l y t i c a g ents i n r a t s : the d e f e n s i v e b u r y i n g paradigm. The growing l i t e r a t u r e c o n c e r n i n g the d e f e n s i v e b u r y i n g phenomenon i n d i c a t e s t h a t r a t s exposed t o a v a r i e t y of a v e r s i v e or n o v e l s t i m u l i w i l l approach the source of thes e s t i m u l i and spray bedding m a t e r i a l or o t h e r s u i t a b l e m a t e r i a l toward or p i l e m a t e r i a l around the s o u r c e of the s t i m u l u s i n such a way as t o 'bury' the s t i m u l u s s o u r c e ( c f . P i n e l & T r e i t , 1978; T e r l e c k i , P i n e l , & T r e i t , 1979). T h i s 166 b e h a v i o u r may be e l i c i t e d by a c o n t i n g e n t p r e s e n t a t i o n of a no x i o u s s t i m u l u s ( e . g . , shock) w i t h an o t h e r w i s e innocous o b j e c t (the c o n d i t i o n e d d e f e n s i v e b u r y i n g p r o c e d u r e ) or by p r e s e n t a t i o n of a complex n o v e l o b j e c t (the u n c o n d i t i o n e d d e f e n s i v e b u r y i n g p r o c e d u r e ) . T r e i t ( P i n e l & T r e i t , i n p r e s s , 1981; T r e i t , 1981) has demonstrated t h a t c l i n i c a l l y u t i l i z e d a n x i o l y t i c agents such as diazepam w i l l reduce both c o n d i t i o n e d and u n c o n d i t i o n e d d e f e n s i v e b u r y i n g i n a dose-dependent manner and has suggested t h a t t h i s r e d u c t i o n i n d e f e n s i v e burying- may w e l l r e f l e c t the a n x i o l y t i c or f e a r - m o d u l a t i n g a c t i o n s of the b e n z o d i a z e p i n e s . I f v e s t i b u l a r s t i m u l a t i o n does have some a n x i o l y t i c or c a l m i n g e f f e c t , then t h i s e f f e c t s h o u l d be d e t e c t a b l e i n the d e f e n s i v e b u r y i n g paradigm as a r e d u c t i o n i n the amount of b u r y i n g b e h a v i o u r e l i c i t e d by a p a r t i c u l a r s t i m u l u s . In the p r e s e n t e x p e r i m e n t , t h e e f f e c t s of abnormal motion on subsequent d e f e n s i v e b e h a v i o u r were s t u d i e d i n the u n c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm d e s c r i b e d by T e r l e c k i e t a l . (1979). T h i s paradigm was chosen as i t does not r e q u i r e the use of shock of or any o t h e r n o x i o u s s t i m u l u s whose f u n c t i o n a l s t r e n g t h c o u l d be a t t e n u a t e d by the motion induced a n a l g e s i a phenomenon d e s c r i b e d p r e v i o u s l y . In a d d i t i o n , the u n c o n d i t i o n e d b u r y i n g t e s t s e s s i o n i s of a f i x e d l e n g t h and can be a d m i n i s t e r e d a t any time f o l l o w i n g the t r e a t m e n t ; whereas, the c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm i n v o l v e s v a r i a b l e d e l a y s from the s t a r t of the t e s t s e s s i o n u n t i l the a v e r s i v e s t i m u l u s i s a d m i n i s t e r e d . T h i s c o n s i s t e n c y i n the u n c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm may be im p o r t a n t i f the c a l m i n g e f f e c t of abnormal motion i s of s h o r t d u r a t i o n . 167 I t i s p o s s i b l e t h a t any e f f e c t of abnormal motion on d e f e n s i v e b u r y i n g b e h a v i o u r may be due t o a g e n e r a l s t r e s s e f f e c t whereby any s t r e s s o r a p p l i e d p r i o r t o t e s t i n g would have the same e f f e c t on b u r y i n g b e h a v i o u r as would abnormal m o t i o n . To examine t h i s p o s s i b i l i t y , a group of a n i m a l s t h a t r e c e i v e d o n l y f o o t s h o c k p r i o r t o t e s t i n g i n t h e u n c o n d i t i o n e d b u r y i n g paradigm were i n c l u d e d i n the p r e s e n t e x p e r i m e n t . METHOD S u b j e c t s T h i r t y n a i v e male hooded r a t s s e r v e d as s u b j e c t s i n the p r e s e n t e x p e r i m e n t . The s u b j e c t s weighed between 250 and 350 gm and were group housed i n hanging cages under a r e v e r s e d 12 hr l i g h t / d a r k c y c l e . Food and water were c o n t i n u o u s l y a v a i l a b l e i n the home cage., P r o c e d u r e On each of the 3 days p r i o r t o t e s t i n g , a l l a n i m a l s underwent 30-min h a b i t u a t i o n s e s s i o n s (see P i n e l & T r e i t , 1978). In each h a b i t u a t i o n s e s s i o n , the r a t s were p l a c e d i n groups of s i x i n t o 43 X 30 X 44 cm P l e x i g l a s t e s t chambers c o n t a i n i n g a p p r o x i m a t e l y 5 cm of commercial bedding m a t e r i a l ( S a n - i - c e l , Paxton P r o c e s s i n g Co.) and were a l l o w e d t o move about f r e e l y . On the f o u r t h day, 10 r a t s were randomly a s s i g n e d t o each of t h r e e t r e a t m e n t c o n d i t i o n s : the motion c o n d i t i o n , a no- t r e a t m e n t c o n t r o l c o n d i t i o n , and a shock c o n d i t i o n . Rats i n the motion c o n d i t i o n were p l a c e d i n r e s t r a i n i n g t u b e s and s u b j e c t e d t o 10 min of the h o r i z o n t a l r o t a t i o n and v e r t i c a l o s c i l l a t i o n motion d e s c r i b e d p r e v i o u s l y . Rats i n the shock c o n d i t i o n were p l a c e d i n a g r i d f l o o r shock chamber and s u b j e c t e d t o a s e r i e s of 20 .8 168 mA, 5 sec d u r a t i o n s c r a m b l e d f o o t s h o c k s spaced 25 sec a p a r t . Rats i n the no-treatment c o n t r o l c o n d i t i o n were merely p l a c e d i n the r e s t r a i n i n g tubes and a l l o w e d t o remain i n the tubes f o r a 10 min p e r i o d (n = 5) or were p l a c e d i n the n o n - f u n c t i o n a l shock a p p a r a t u s f o r a 10 min p e r i o d (n = 5 ) . Data from these two groups were combined i n the a n a l y s i s of the r e s u l t s . W i t h i n 2 min of the t e r m i n a t i o n of the t r e a t m e n t p e r i o d , each r a t was p l a c e d i n the c e n t r e of a t e s t chamber c o n t a i n i n g 5 cm of bedding m a t e r i a l and an unset mousetrap a f f i x e d t o the c e n t r e of one w a l l , 2 cm above the l e v e l of the bedding m a t e r i a l ( c f . T e r l e c k i e t a l . , 1979). The b e h a v i o u r of the r a t was m o n i t o r e d from o u t s i d e the room by c l o s e d c i r c u i t t e l e v i s i o n and b u r y i n g b e h a v i o u r was s c o r e d t hroughout the 15 min t e s t s e s s i o n . B u r y i n g b e h a v i o u r i s e a s i l y o b s e r v e d and i s h i g h l y s t e r e o t y p e d : r a t s o r i e n t towards the t r a p and push or spray bedding m a t e r i a l a t i t w i t h r a p i d p u s h i n g movements of the forepaws ( P i n e l & T r e i t , 1978). The d u r a t i o n of b u r y i n g s c o r e r e p o r t e d here was the c u m u l a t i v e d u r a t i o n of a l l i n s t a n c e s of d i r e c t e d f o r e l i m b s p r a y i n g t h a t o c c u r r e d t h r o u g h o u t the t e s t s e s s i o n . F o l l o w i n g the 15-min t e s t s e s s i o n , an a d d i t i o n a l measure of b u r y i n g b e h a v i o u r was o b t a i n e d by measuring the h e i g h t of bedding m a t e r i a l t h a t had accumulated a t the p r o d . RESULTS As shown i n F i g u r e 23, the abnormal motion t r e a t m e n t a d m i n i s t e r e d p r i o r t o exposure t o a n o v e l o b j e c t r e s u l t e d i n an almost complete s u p p r e s s i o n of d e f e n s i v e b u r y i n g b e h a v i o u r . Only one of the 10 r a t s i n the motion t r e a t m e n t c o n d i t i o n demonstrated a s i n g l e b u r s t of b u r y i n g and the d u r a t i o n 169 FIGURE 23. E f f e c t s of p r e - e x p o s u r e t o b r i e f p e r i o d s of abnormal motion (MOT), e l e c t r i c shock (SHK), or a c o n t r o l c o n d i t i o n (CONT) on d e f e n s i v e b u r y i n g b e h a v i o u r i n r a t s (Experiment 1 5 ) . P a n e l A i l l u s t r a t e s d u r a t i o n of b u r y i n g s c o r e s and P a n e l B i n d i c a t e s the h e i g h t of m a t e r i a l accumulated a t the t r a p a t the end of the t e s t s e s s i o n . 170 MEAN HEIGHT OF MATERIAL (cm) oo CQ Is- CD LO I-Z o o X CO O 1 o o X CO r -o o co I o C\J o (09s) oNiAana do Nonvana NVBI/M 171 of t h i s b u r s t (1.9 sec) was i n s u f f i c i e n t t o a l t e r the h e i g h t s c o r e . R a t s i n the shock and no-t r e a t m e n t c o n t r o l c o n d i t i o n s , on the o t h e r hand, showed a p p r e c i a b l e amounts of b u r y i n g b e h a v i o u r . One-way a n a l y s i s of v a r i a n c e f o r each measure c o n f i r m e d a s i g n i f i c a n t t r e a t m e n t e f f e c t (F=4.54, df=2/27, p<.05 f o r d u r a t i o n ; F=5.06, df=2/27, p<.05 f o r h e i g h t ) and post-hoc a n a l y s i s (Tukey) i n d i c a t e d t h a t s c o r e s i n the motion c o n d i t i o n were s i g n i f i c a n t l y l e s s than those i n the shock or c o n t r o l c o n d i t i o n s . Post-hoc a n a l y s i s f u r t h e r i n d i c a t e d t h a t shock and c o n t r o l group s c o r e s d i d not d i f f e r s i g n i f i c a n t l y i n e i t h e r the d u r a t i o n or h e i g h t measure. DISCUSSION The r e s u l t s of the p r e s e n t experiment i n d i c a t e t h a t exposure t o a b r i e f p e r i o d (10 min) of abnormal motion r e s u l t s i n a d r a m a t i c a l t e r a t i o n i n the r a t ' s subsequent r e a c t i o n t o a n o v e l o b j e c t . Rats t h a t had e x p e r i e n c e d a p e r i o d of abnormal motion e x h i b i t e d almost no d e f e n s i v e b u r y i n g b e h a v i o u r i n response t o an unset mousetrap, a s t i m u l u s t h a t was e f f e c t i v e i n e l i c i t i n g b u r y i n g b e h a v i o u r i n r a t s t h a t had been pre-exposed t o e i t h e r a p e r i o d of f o o t s h o c k or t o a c o n t r o l c o n d i t i o n . T h i s a t t e n u a t i o n i n d e f e n s i v e b u r y i n g b e h a v i o u r may r e p r e s e n t an e m p i r i c a l d e m o n s t r a t i o n of the p u t a t i v e a n x i o l y t i c or c a l m i n g e f f e c t s of abnormal m o t i o n . I t i s c l e a r t h a t the a t t e n u a t i o n was s p e c i f i c t o abnormal motion and was not mer e l y a g e n e r a l e f f e c t of pr e - e x p o s u r e t o a n o x i o u s or " s t r e s s f u l " s t i m u l u s . T r e i t ( P i n e l & T r e i t , i n p r e s s , 1981; T r e i t , 1981) has d e m o n s t r a t e d a s i m i l a r s u p p r e s s i o n of b u r y i n g b e h a v i o u r f o l l o w i n g p r e - t r e a t m e n t w i t h drugs t h a t a r e used c l i n i c a l l y f o r 172 t h e i r a n x i o l y t i c e f f e c t s (e.g. diazepam, c h l o r d i a z e p o x i d e ) . Other c l a s s e s of drugs such as s t i m u l a n t s (amphetamine, p i c r o t o x i n ) or major t r a n q u i l i z e r s ( c h l o r p r o m a z i n e ) e i t h e r had no e f f e c t on d e f e n s i v e b u r y i n g b e h a v i o u r , caused a s l i g h t i n c r e a s e i n the amount of b u r y i n g b e h a v i o u r , or produced p a t t e r n s of e f f e c t s on d e f e n s i v e b u r y i n g which were d i f f e r e n t from the e f f e c t s of the a n x i o l y t i c a g e n t s . I t would seem p o s s i b l e t h e n , t h a t abnormal motion r e p r e s e n t s a n o n - p h a r m a c o l o g i c a l means f o r the c o n t r o l of a n x i e t y or f e a r . That i s , abnormal motion may a c t i v a t e an endogenous a n x i o l y t i c mechanism. There are however, a number of d i f f i c u l t i e s a s s o c i a t e d w i t h t h i s i n t e r p r e t a t i o n . F i r s t , i t i s p o s s i b l e t h a t some o t h e r e f f e c t of abnormal motion o t h e r than an a n x i o l y t i c e f f e c t i s r e s p o n s i b l e f o r the s u p p r e s s i o n of b u r y i n g observed i n the p r e s e n t e x p e r i m e n t . The abnormal motion may have produced a g r o s s motor d e f i c i t i n the subsequent t e s t . I f the r a t s were d i z z y f o r example, one would expect t h e i r a b i l i t y t o m a n i p u l a t e the bedding m a t e r i a l t o be somewhat i m p a i r e d . A l t h o u g h t h i s h y p o t h e s i s cannot be e l i m i n a t e d , i t i s u n l i k e l y t h a t the motor d e f i c i t or ' d i z z i n e s s ' would p e r s i s t f o r the e n t i r e 15-min t e s t p e r i o d (see a l s o S e c t i o n s I I and I I I ) . O b s e r v a t i o n s of the t e s t s e s s i o n a l s o suggest t h a t a l t h o u g h o v e r a l l a c t i v i t y l e v e l s appeared somewhat s u p p r e s s e d , the a n i m a l s i n the motion c o n d i t i o n walked about t h e chambers w i t h l i t t l e a p parent d i f f i c u l t y . I t i s a l s o p o s s i b l e t h a t the r a t s had been made ' i l l ' as a r e s u l t of exposure t o abnormal m o t i o n . Abnormal motion does appear c a p a b l e of .producing some i n t e r n a l s t a t e t h a t i s c a p a b l e of s u p p o r t i n g a 173 c o n d i t i o n e d t a s t e a v e r s i o n (see E x p e r i m e n t s 13 and 14) and t h i s i n t e r n a l s t a t e (motion s i c k n e s s ? ) may have produced a s u p p r e s s i o n of b u r y i n g b e h a v i o u r . T h i s a l t e r n a t i v e e x p l a n a t i o n a g a i n cannot be e l i m i n a t e d but appears u n l i k e l y f o r two r e a s o n s . F i r s t , motion i n d u c e d i l l n e s s decays r a p i d l y f o l l o w i n g c e s s a t i o n of the motion s t i m u l u s (Reason & G r a y b i e l , 1970) and i t i s u n l i k e l y the r a t s were d e b i l i t a t e d t o an e x t e n t t h a t would p r e v e n t b u r y i n g f o r the e n t i r e 15-min t e s t p e r i o d . O b s e r v a t i o n s a g a i n i n d i c a t e d the r a t s d i d not appear t o be s u f f e r i n g g r o s s d e b i l i t a t i o n . Second, T r e i t (1981) i n d i c a t e s t h a t drugs t h a t a r e c a p a b l e of p r o d u c i n g i l l n e s s and t a s t e a v e r s i o n s i n r a t s do not have c o n s i s t e n t e f f e c t s on d e f e n s i v e b u r y i n g . S t i m u l a n t s such as amphetamine f o r example, do not s u p p r e s s b u r y i n g but do produce c o n d i t i o n e d t a s t e a v e r s i o n s , even i n doses t h a t a n i m a l s w i l l s e l f - a d m i n i s t e r (Gamzu, 1975). I t seems u n l i k e l y t h e n , t h a t i l l n e s s would have any c o n s i s t e n t e f f e c t on d e f e n s i v e b u r y i n g . The r e s u l t s and c o n c l u s i o n s of the p r e s e n t experiment must be c o n s i d e r e d p r e l i m i n a r y i n terms of a n o n - p h a r m a c o l o g i c a l a n x i o l y t i c mechanism. The p o s s i b l e a n x i o l y t i c e f f e c t s of abnormal motion c o u l d be more c l e a r l y d e l i n e a t e d i n a v a r i e t y of ways. The c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm f o r example, has been used by P i n e l and T r e i t ( i n p r e s s , 1981) t o c o n t r o l f o r p o s s i b l e i n t e r f e r i n g s i d e e f f e c t s of drugs i n the b e n z o d i a z e p i n e - i n d u c e d s u p p r e s s i o n of b u r y i n g phenomenon. Drug-t r e a t e d r a t s r e c e i v e d e i t h e r a low or h i g h i n t e n s i t y shock from a p r o d mounted on the w a l l of the t e s t chamber. B e n z o d i a z e p i n e s , i n a v a r i e t y of doses, d i d not s u p p r e s s b u r y i n g 174 a t the h i g h shock l e v e l whereas b u r y i n g e l i c i t e d by the low shock l e v e l was s u p p r e s s e d . The f a c t t h a t a n x i o l y t i c drugs d i d not a f f e c t b u r y i n g b e h a v i o u r e l i c i t e d by a h i g h shock l e v e l a l l o w e d g r o s s motor impairment and o t h e r p o s s i b l e s i d e e f f e c t s (such as a n a l g e s i a ) t o be e l i m i n a t e d as e x p l a n a t i o n s f o r the e f f e c t s of a n x i o l y t i c d r u g s . A s i m i l a r a n a l y s i s c o u l d be conducted f o r the e f f e c t s of abnormal motion on d e f e n s i v e b u r y i n g . The s p e c i f i c i t y of the p o s s i b l e a n x i o l y t i c e f f e c t s of abnormal motion c o u l d be e s t a b l i s h e d by t e s t i n g the e f f e c t s of abnormal motion i n b e h a v i o u r a l paradigms t h a t a r e used as s c r e e n i n g d e v i c e s f o r a n x i o l y t i c d r u g s . The reader i s r e f e r r e d t o G l i c k (1976) f o r an o v e r v i e w of t h e s e t e c h n i q u e s . I t would seem t h a t both of t h e s e s t e p s must be completed b e f o r e any f i r m a nalogy i s drawn between the b e h a v i o u r a l e f f e c t s of abnormal motion and the e f f e c t s of c l i n i c a l a n x i o l y t i c a g e n t s , and thus the p r e s e n t r e s u l t s r e p r e s e n t a p r e l i m i n a r y s t a g e i n the i n v e s t i g a t i o n of n o n - p h a r m a c o l o g i c a l a n x i o l y t i c mechanisms. I t i s t e m p t i n g however, t o s p e c u l a t e on the p o s s i b l e u n d e r l y i n g mechanisms f o r a n o n - p h a r m a c o l o g i c a l a n x i o l y t i c phenomenon. There are a r e l e a s t two e x c i t i n g p o s s i b i l i t i e s f o r t h i s mechanism. The f i r s t of t h e s e i n v o l v e s endogenous o p i a t e p e p t i d e s . The e x p e r i m e n t s c o n t a i n e d i n p r e v i o u s p o r t i o n s of t h i s t h e s i s s t r o n g l y i n d i c a t e t h a t endogenous o p i a t e a c t i v i t y i s enhanced by abnormal m o t i o n . Endogenous o p i a t e p e p t i d e s have been su g g e s t e d t o p l a y an a n t i - a n x i e t y r o l e i n humans. G r e v e r t and G o l d s t e i n (1977) have found t h a t human s u b j e c t s r e c e i v i n g 175 naloxone showed more a n x i e t y , t e n s i o n , and h o s t i l i t y on s t a n d a r d mood s c a l e s than d i d s a l i n e - t r e a t e d s u b j e c t s a f t e r exposure t o a s t r e s s f u l s i t u a t i o n . Presumably, the s t r e s s f u l s i t u a t i o n a c t i v a t e d an e n d o r p h i n mechanism which was r e s p o n s i b l e f o r the change i n mood i n the s a l i n e c o n t r o l s but was b l o c k e d i n the n a l o x o n e - t r e a t e d s u b j e c t s . Naloxone a d m i n i s t r a t i o n t o human p a t i e n t s i n o t h e r s t u d i e s ( G r e v e r t & G o l d s t e i n , 1978) has a l s o been r e p o r t e d t o r e s u l t i n vague f e e l i n g s of a n x i e t y and t e n s i o n t h a t d i d not r e s u l t from t r e a t m e n t w i t h a s a l i n e v e h i c l e . Morphine, the p r o t o t y p i c a l o p i a t e a n g o n i s t , a l s o appears t o e x e r t some a n x i o l y t i c a c t i o n s i n a d d i t i o n t o i t s many o t h e r e f f e c t s ( J a f f e & M a r t i n , 1975; T e r e n i u s , 1978). P i l o t s t u d i e s a t t e m p t i n g t o b l o c k the m o t i o n - i n d u c e d s u p p r e s s i o n of b u r y i n g b e h a v i o u r w i t h naloxone i n our l a b o r a t o r y however, have thus f a r been u n s u c c e s s f u l . Another p o s s i b l e mechanism f o r the m o t i o n - i n d u c e d s u p p r e s s i o n of b u r y i n g b e h a v i o u r i n v o l v e s the r e c e n t d i s c o v e r y of b e n z o d i a z e p i n e - s p e c i f i c r e c e p t o r s i n the b r a i n ( T a l l m a n , P a u l , S k o l n i k , & G a l l a g e r , 1980). The presence of b e n z o d i a z e p i n e r e c e p t o r s s u g g e s t s t h a t an endogenous b e n z o d i a z e p i n e m o l e c u l e may a l s o e x i s t w i t h i n the c e n t r a l nervous system. A l t h o u g h t h i s endogenous l i g a n d has not y e t been i d e n t i f i e d , i t i s p o s s i b l e t h a t an endogenous " a n t i -a n x i e t y " system e x i s t s w i t h i n the b r a i n and may be a c t i v a t e d by s t i m u l i such as abnormal mot i o n . In c o n c l u s i o n , i t appears t h a t abnormal motion may have an i d e n t i f i a b l e a n x i o l y t i c or c a l m i n g e f f e c t . A l t h o u g h the r e s u l t s d e s c r i b e d here a re p r o v o c a t i v e , and much more r e s e a r c h i s 176 n e c e s s a r y t o q u a n t i f y and d e s c r i b e the n a t u r e of t h e s e e f f e c t s , they do r a i s e the i n t e r e s t i n g and p o t e n t i a l l y u s e f u l p o s s i b i l i t y of the c o n t r o l of c l i n i c a l a n x i e t y syndromes t h r o u g h non-p h a r m a c o l o g i c a l means. 177 GENERAL DISCUSSION The p r e s e n t t h e s i s has uncovered and i n v e s t i g a t e d a v a r i e t y of b e h a v i o u r a l e f f e c t s t h a t o ccur i n response t o a b r i e f p e r i o d of abnormal motion i n r a t s . These b e h a v i o u r a l e f f e c t s i n c l u d e a n a l g e s i a , a v e r s i o n t o a p r e v i o u s l y p r e f e r r e d t a s t e , and a p o s s i b l e a n x i o l y t i c e f f e c t . S e c t i o n s I , I I , and I I I of the p r e s e n t i n v e s t i g a t i o n were devoted p r i m a r i l y t o e x p l o r i n g the a n t i n o c i c e p t i v e e f f e c t s of exposure t o abnormal motion and the p h y s i o l o g i c a l mechanisms u n d e r l y i n g t h i s newly d i s c o v e r e d e f f e c t . S e c t i o n I c o n f i r m e d the e a r l i e r i n d i c a t i o n s from our l a b o r a t o r y of the e x i s t e n c e of an a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n r a t s . T h i s a n t i n o c i c e p t i v e e f f e c t was found f o l l o w i n g o n l y r e l a t i v e l y complex forms of abnormal motion and was of a r e l a t i v e l y b r i e f d u r a t i o n when compared t o o t h e r forms of n o n - p h a r m a c o l o g i c a l p a i n m o d u l a t i o n ( e . g . Hayes, Bennet, Newlon, & Mayer, 1978). The h o t - w a t e r t a i l w i t h d r a w a l t e s t was used as the p r i m a r y measure of a n a l g e s i a but the a n a l g e s i a produced by abnormal motion was not r e s t r i c t e d t o t h i s one measure of a n a l g e s i a as a s i g n i f i c a n t a n t i n o c i c e p t i v e e f f e c t was a l s o found i n the h o t -p l a t e p a w - l i c k jump-escape t a s k . I t was a l s o found t h a t the a n a l g e s i c e f f e c t of abnormal motion r e q u i r e d some m i n i m a l p e r i o d of exposure t o the motion i n o r d e r t o appear (or be d e t e c t e d ) i n the a n a l g e s i a t e s t and once the a n a l g e s i c e f f e c t had • d e v e l o p e d , l i t t l e change i n i t s magnitude was apparent w i t h l o n g e r p e r i o d s of exposure t o the motion. S e c t i o n I I was devoted t o i n v e s t i g a t i n g the r o l e of the v e s t i b u l a r system i n the m o d u l a t i o n of the a n t i n o c i c e p t i v e 178 e f f e c t of abnormal mot i o n . D e s t r u c t i o n of the p e r i p h e r a l v e s t i b u l a r a p p a r a t u s c o m p l e t e l y e l i m i n a t e d the a n t i n o c i c e p t i v e response t o a p e r i o d of abnormal m o t i o n , thus i m p l i c a t i n g the v e s t i b u l a r system i n a n t i n o c i c e p t i o n produced by abnormal motion. L e s i o n s and e l e c t r i c a l s t i m u l a t i o n of some d i s c r e t e components of the c e n t r a l v e s t i b u l a r system however, r e v e a l e d no c o n s i s t e n t i n v o l v e m e n t of any s i n g l e c e n t r a l v e s t i b u l a r component. These r e s u l t s were i n t e r p r e t e d t o suggest t h a t a l t h o u g h the v e s t i b u l a r system i s e s s e n t i a l f o r the p r o d u c t i o n of the p a i n m o d u l a t i n g e f f e c t of abnormal motio n , more than one or d i f f e r e n t c e n t r a l v e s t i b u l a r components a r e p r o b a b l y i n v o l v e d . S e c t i o n I I I p r e s e n t e d c o n c r e t e e v i d e n c e t h a t t h i s a n t i n o c i c e p t i v e e f f e c t i s mediated by an endogenous o p i a t e p a i n m o d u l a t i n g mechanism. The a n t i n o c i c e p t i v e e f f e c t of abnormal motion was b l o c k e d by the o p i a t e a n t a g o n i s t drug naloxone and a l s o demonstrated c r o s s - t o l e r a n c e w i t h c h r o n i c morphine a d m i n i s t r a t i o n . U n l i k e some o t h e r forms of n o n - p h a r m a c o l o g i c a l or s t r e s s - i n d u c e d a n t i n o c i c e p t i o n (Bodnar, K e l l y , & Glusman, 1979; Chance & R o s e c r a n s , 1979; L e w i s , Cannon, & L i e b e s k i n d , 1980; S p i a g g i a , Bodnar, K e l l y , & Glusman, 1979), m o t i o n - i n d u c e d a n a l g e s i a appears t o be produced t h r o u g h a mechanism t h a t i n v o l v e s endogenous o p i a t e p e p t i d e s . The e x a c t l o c u s of t h i s o p i a t e p e p t i d e mechanism was not found, a l t h o u g h i t i s a p p a r e n t l y independent of the h y p o t h a l a m i c - p i t u i t a r y a x i s u n l i k e o t h e r a p p a r e n t l y o p i a t e - r e g u l a t e d forms of n o n - p h a r m a c o l o g i c a l p a i n m o d u l a t i o n (Cheng & Pomeranz, 1978; Cheng, Pomeranz, & Yu, 1979). 179 S e c t i o n IV i n v e s t i g a t e d a p o s s i b l e i m p l i c a t i o n of the a c t i v a t i o n of an endogenous o p i a t e system i n response t o abnormal m o t i o n . There a r e a number of s i m i l a r i t i e s between the e f f e c t s of exogenous o p i a t e a d m i n i s t r a t i o n and the symptoms and s i g n s of motion s i c k n e s s and t h i s s i m i l a r i t y s uggested t h a t motion s i c k n e s s c o u l d be mediated by an endogenous o p i a t e mechanism. Exposure t o abnormal motion produced a d r a m a t i c a v e r s i o n t o a p r e f e r r e d n o v e l f l u i d a f t e r p a i r i n g of the f l u i d and abnormal motion. However, o p i a t e a n t a g o n i s t s were u n s u c c e s s f u l i n b l o c k i n g a mot i o n - i n d u c e d c o n d i t i o n e d t a s t e a v e r s i o n , a p u t a t i v e rodent analogue of motion s i c k n e s s . A l s o i n c l u d e d i n t h i s s e c t i o n was a p r e l i m i n a r y i n v e s t i g a t i o n of a p o s s i b l e " c a l m i n g " or " a n x i o l y t i c " e f f e c t of v e s t i b u l a r s t i m u l a t i o n . A b r i e f p e r i o d of abnormal motion was found t o s u p p r e s s performance of a s p e c i e s - t y p i c a l d e f e n s i v e r e s p o n s e : d e f e n s i v e b u r y i n g . These r e s u l t s a r e c o n s i s t e n t w i t h the e f f e c t s of a n x i o l y t i c drugs on the d e f e n s i v e b u r y i n g response and s u g g e s t , somewhat p r e m a t u r e l y perhaps, t h a t an endogenous a n x i o l y t i c mechanism may be a c t i v a t e d by v e s t i b u l a r s t i m u l a t i o n . From t h i s b r i e f r e v i e w of the f i n d i n g s of the p r e s e n t t h e s i s , i t would seem t h a t t h e r e a re a v a r i e t y of i m p l i c a t i o n s of t h e s e f i n d i n g s f o r p a i n c o n t r o l , motion s i c k n e s s , and a p o s s i b l e endogenous a n x i o l y t i c mechanism. T h i s f i n a l s e c t i o n of the t h e s i s i s devoted t o a d i s c u s s i o n of t h e s e i m p l i c a t i o n s and p o s s i b l e a p p l i c a t i o n s . T h i s g e n e r a l d i s c u s s i o n i s d i v i d e d i n t o t h r e e s e p a r a t e p a r t s , each a d i s c u s s i o n of the t h r e e main s u b j e c t a r e a s i n v e s t i g a t e d h e r e : p a i n m o d u l a t i o n , motion s i c k n e s s , and a n x i e t y m o d u l a t i o n . 180 MOTION-INDUCED ANTINOCICEPTION Exposure t o a b r i e f p e r i o d of abnormal motion a c t i v a t e s an endogenous o p i a t e system t h a t appears r e s p o n s i b l e f o r the a n t i n o c i c e p t i v e e f f e c t s of motion o b s e r v e d i n the ho t - w a t e r t a i l w i t h d r a w a l and hot p l a t e t e s t s . The s i g n i f i c a n c e of t h i s f i n d i n g f o r endogenous p a i n m o d u l a t i o n mechanisms and p o s s i b l e a p p l i c a t i o n s t o p a i n c o n t r o l a r e d i s c u s s e d below. P h y s i o l o g i c a l mechani sms of mot i o n - i n d u c e d a n t i n o c i c e p t i o n E x p e r i m e n t s 9, 10, and 11 of S e c t i o n I I I s t r o n g l y i m p l i c a t e an endogenous o p i a t e p a i n m o d u l a t i o n system i n the a n t i n o c i c e p t i v e e f f e c t of abnormal mot i o n . Naloxone a t v e r y low doses (0.5 mg/kg) c o m p l e t e l y b l o c k e d the a n t i n o c i c e p t i v e e f f e c t of abnormal motion and the a n t i n o c i c e p t i v e e f f e c t demonstrated c r o s s - t o l e r a n c e w i t h c h r o n i c morphine t r e a t m e n t , thus s u g g e s t i n g s i m i l a r mechanisms f o r morphine and m o t i o n - i n d u c e d a n a l g e s i a . A l t h o u g h e n d o r p h i n s appear t o be i n v o l v e d i n m e d i a t i n g the p a i n -m o d u l a t i n g p r o p e r t i e s of abnormal m o t i o n , i t i s not c l e a r which s p e c i f i c o p i a t e p e p t i d e s a r e i n v o l v e d or where i n the nervous system they a r e e x e r t i n g t h i s m o d u l a t i n g i n f l u e n c e on p a i n t r a n s m i s s i o n . There a r e t h r e e endogenous o p i a t e p e p t i d e s t h a t have been i m p l i c a t e d i n endogeous p a i n m o d u l a t i o n : B - e n d o r p h i n , met-e n k e p h a l i n , and l e u - e n k e p h a l i n ( B a r c h a s , A k i l , E l l i o t , Holman, & Watson, 1978; Basbaum & F i e l d s , 1978; B i s h o p , 1980; K o s t e r l i t z , 1979; L i e b e s k i n d , 1978). The e n k e p h l i n s , met- and l e u -e n k e p h a l i n , a r e thought t o be degraded e x t r e m e l y r a p i d l y i n the nervous sytem and hence produce a n a l g e s i a of r e l a t i v e l y s h o r t d u r a t i o n ( F r e d e r i c k s o n , S m i t h w i c k , & Shuman, 1978; M i l l e r & 181 C u a t r e c a s a s , 1979). In c o n t r a s t , B-endorphin i s degraded v e r y s l o w l y and produces a l o n g - l a s t i n g a n a l g e s i c e f f e c t ( R o s s i e r & Bloom, 1979; Tseng, Loh, & L i , 1976). Based on a n a l g e s i c p o t e n c y , B-endorphin i s c o n s i d e r e d t o be more p o t e n t than morphine when compared on a molar b a s i s (Tseng, Loh, & L i , 1976; Yaksh & Henry, 1978). The s h o r t d u r a t i o n of the a n a l g e s i c e f f e c t of abnormal motion demonstrated i n S e c t i o n I and the f a c t t h a t motion d i d not at any time produce a degree of a n a l g e s i a i n any way comparable t o t h a t produced by morphine, would seem t o suggest t h a t i t i s the e n k e p h a l i n s r a t h e r than B-endorphin t h a t a r e r e s p o n s i b l e f o r the a n a l g e s i c e f f e c t s of abnormal motion. A d d i t i o n a l s u p p o r t f o r t h i s h y p o t h e s i s i s p r o v i d e d by the f a i l u r e t o f i n d an e f f e c t of adrenalectomy on the m o t i o n - i n d u c e d a n a l g e s i a phenomenon i n Experiment 12. B-endorphin i s r e s t r i c t e d almost e x c l u s i v e l y t o the p i t u i t a r y g l a n d (Barchas e t a l . , 1978; R o s s i e r & Bloom, 1979) and i s thought t o be s e c r e t e d c o n c o m i t a n t l y w i t h ACTH ( G u i l l e m i n , Vargo, R o s s i e r , M i n i c k , L i n g , R i v i e r , V a l e , & Bloom, 1977). Any m a n i p u l a t i o n s t h a t a f f e c t the r e g u l a t i o n of ACTH s e c r e t i o n s h o u l d thus a f f e c t c i r c u l a t i n g l e v e l s of B-endorphin and mask or e l i m i n a t e the a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n . Cheng, Pomeranz, and Yu (1979) f o r example, have shown t h a t n a l o x o n e - r e v e r s i b l e a c u p u n c t u r e a n a l g e s i a i s a t t e n u a t e d by p r e t r e a t m e n t w i t h dexamethasone, a s y n t h e t i c g l u c o c o r t i c o i d t h a t a c t s t o suppress ACTH s e c r e t i o n t h r o u g h a feedback mechanism i n the hypothalamus ( M a r t i n i , M o t t a , & M u l l e r , 1964)'. T h i s i n h i b i t i o n of ACTH s e c r e t i o n , and thus B-endorphin s e c r e t i o n , from the p i t u i t a r y i s thought t o e x p l a i n the a t t e n u a t i o n of a n a l g e s i a . 182 A drenalectomy, which i n c r e a s e s ACTH s e c r e t i o n ( M a r t i n i , M o t t a , & M u l l e r , 1964), had no e f f e c t on the appearance of the mot i o n - i n d u c e d a n a l g e s i a phenomenon i n the p r e s e n t e x p e r i m e n t s . The l a c k of e f f e c t of adrenalectomy t h e n , would suggest t h a t B-e n d o r p h i n i s not i n v o l v e d i n the a n t i n o c i c e p t i v e e f f e c t of abnormal motion and, by e l i m i n a t i o n , i m p l i c a t e s the e n k e p h a l i n s . I f one can e l i m i n a t e B-endorphin as the endogenous o p i o i d p e p t i d e i n v o l v e d i n the a n t i n o c i c e p t i v e e f f e c t , i t would seem l i k e l y t h a t the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s mediated t h r o u g h a c e n t r a l nervous system mechanism t h a t does not i n v o l v e the h y p o t h a l a m i c - p i t u i t a r y a x i s . Hence, the a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s most l i k e l y produced by an e n k e p h a l i n e r g i c p a i n m o d u l a t i n g system l o c a t e d w i t h i n the c e n t r a l nervous system. C o n c e n t r a t i o n s of e n k e p h a l i n e r g i c neurons a r e found i n c o n j u n c t i o n w i t h p a i n pathways (Basbaum & F i e l d s , 1978; Kuhar & U h l , 1979) t hroughout the a s c e n d i n g p a l e o s p i n a l t h a l a m i c system. The p a l e o s p i n a l t h a l a m i c system i s thought t o p r e d o m i n a n t l y c a r r y i n f o r m a t i o n c o n c e r n i n g 'slow' or ' b u r n i n g ' p a i n r a t h e r than ' f a s t ' p a i n ( A d l e r , 1980; Basbaum & F i e l d s , 1978; K o s t e r l i t z , 1979; P e r t , 1978). L a r g e c o n c e n t r a t i o n s of e n k e p h a l i n e r g i c neurons a r e found i n the s u b s t a n t i a g e l a t i n o s a of the s p i n a l c o r d and a t v a r i o u s o t h e r p o i n t s t hroughout the a s c e n d i n g c o u r s e of the s p i n o t h a l a m i c pathway (Basbaum & F i e l d s , 1978; Kuhar & U h l , 1979). Any one or a l l of t h e s e groups of e n k e p h a l i n e r g i c neurons c o u l d modulate the t r a n s m i s s i o n of p a i n i n f o r m a t i o n i n t h i s pathway, and the s t u d i e s c o n t a i n e d w i t h i n the p r e s e n t t h e s i s a l l o w no f u r t h e r l o c a l i z a t i o n of t h i s m o d u l a t i n g e f f e c t . 183 No d i r e c t a n a t o m i c a l l i n k has been e s t a b l i s h e d between the p a i n pathways and the v e s t i b l u l a r system ( a l t h o u g h some i n t e r a c t i o n i n the r e t i c u l a r f o r m a t i o n i s p o s s i b l e ) . P o s s i b l e mechanisms f o r the m o d u l a t i o n of p a i n t r a n s m i s s i o n i n the c e n t r a l nervous system have been e x t e n s i v e l y d i s c u s s e d elsewhere ( M e l z a c k , 1973; Melzack & W a l l , 1968; Nathan, 1976) and the reader i s r e f e r r e d t o t h e s e s o u r c e s f o r a comprehensive t r e a t m e n t of t h i s t o p i c . I t was suggested i n S e c t i o n I I I of the p r e s e n t t h e s i s t h a t the mot i o n - i n d u c e d a n a l g e s i a phenomenon may r e p r e s e n t a phenomenon analogous t o the " s t r e s s - i n d u c e d a n a l g e s i a " (SIA) phenomenon t h a t has been the t a r g e t of i n t e n s i v e r e s e a r c h a c t i v i t y i n r e c e n t y e a r s . The purpose of the f o l l o w i n g s e c t i o n i s t o examine c u r r e n t f i n d i n g s c o n c e r n i n g s t r e s s - i n d u c e d a n a l g e s i a and t h e i r r e l a t i o n s h i p t o the m o t i o n - i n d u c e d a n a l g e s i a phenomenon. S t r e s s - i n d u c e d and mot i o n - i n d u c e d a n a l g e s i a . R e c e n t l y , a g r e a t d e a l of i n t e r e s t has been g e n e r a t e d by the f i n d i n g t h a t a s h o r t p e r i o d of f o o t s h o c k i s s u f f i c i e n t t o induce a n t i n o c i c e p t i o n i n the r a t ( A k i l , Madden, P a t r i c k , & B a r c h a s , 1976). T h i s study was one of the f i r s t t o c l e a r l y d emonstrate the e x i s t e n c e of a n o n - p h a r m a c o l g i c a l p a i n c o n t r o l mechanism t h a t c o u l d be a c t i v a t e d by p h y s i o l o g i c a l ' s t r e s s ' . S i n c e p u b l i c a t i o n of t h i s s t u d y , a l a r g e number of a d d i t i o n a l i n v e s t i g a t i o n s of s t r e s s - i n d u c e d a n a l g e s i a have been performed. The r e s u l t s of the s e s t u d i e s p r e s e n t a r a t h e r c o m p l i c a t e d r o l e f o r ' s t r e s s ' i n the SIA phenomenon and a l s o suggest t h a t d i f f e r e n t p h y s i o l o g i c a l s t r e s s o r s may a c t i v a t e one or a number of a n t i n o c i c e p t i v e mechanisms. 184 Bodnar and h i s co-workers (Bodnar, K e l l y , B r u t u s , Greenman, & Glusman, 1980; S p i a g g i a , Bodnar, K e l l y , & Glusman, 1979) have suggested t h a t endogenous p a i n m o d u l a t i o n may be mediated by one or both of two d i f f e r e n t t y p e s of systems: one o p i a t e i n n a t u r e and the o t h e r n o n - o p i a t e . In the f o l l o w i n g b r i e f r e v i e w , t h e s e systems w i l l be c o n s i d e r e d s e p a r a t e l y and the t y p e s of s t r e s s o r s thought t o a c t i v a t e them w i l l be d i s c u s s e d . Endogenous o p i a t e mechanisms. An endogenous o p i a t e p a i n m o d u l a t i o n system has been proposed t o account f o r the a n t i n o c i c e p t i v e e f f e c t s of a v a r i e t y of d i f f e r e n t t y p e s of s t r e s s o r s . In most of t h e s e , the a n a l g e s i c e f f e c t s of the p a r t i c u l a r s t r e s s o r have been shown t o be r e v e r s i b l e w i t h the o p i a t e a n t a g o n i s t n a l o x o n e , and i n some c a s e s , c r o s s - t o l e r a n c e w i t h morphine has been e s t a b l i s h e d . E l e c t r o a c u p u n c t u r e (Cheng & Pomeranz, 1978), i m m o b i l i z a t i o n (Amir & Amit, 1978), e l e c t r i c a l b r a i n s t i m u l a t i o n ( A k i l , Mayer, & L i e b e s k i n d , 1976), food d e p r i v a t i o n (McGivern, B e r k a , B e r n t s o n , Walker, & Sandman, 1979) and f o o t s h o c k ( B u c k e t t , 1979) a r e a l l t r e a t m e n t s t h a t a r e thought t o produce an o p i a t e mediated a n t i n o c i c e p t i v e e f f e c t . A d d i t i o n a l s u p p o r t f o r o p i a t e i n v o l v e m e n t a r i s e s from s t u d i e s d e m o n s t r a t i n g i n c r e a s e d e n d o r p h i n l e v e l s ( e . g . A k i l , Madden, P a t r i c k , & B a r c h a s , 1976; T e r e n i u s , 1978), and d e c r e a s e d r e c e p t o r b i n d i n g c a p a c i t y (Chance, W h i t e , Krynock, & R o s e c r a n s , 1978; D e V r i e s , Chance, Payne, & R o s e c r a n s , 1979) f o l l o w i n g exposure t o s t r e s s o r s and an a t t e n u a t i o n of the a n a l g e s i c e f f e c t s of s t r e s s o r s f o l l o w i n g t r e a t m e n t s t h a t reduce e n d o r p h i n l e v e l s (Cheng, Pomeranz, & Yu, 1979). The a n t i n o c i c e p t i v e e f f e c t of abnormal motion d i s c u s s e d i n 185 the p r e s e n t t h e s i s a l s o seems t o f i t i n the c a t e g o r y of an e n d o r p h i n - m e d i a t e d a n t i n o c i c e p t i v e e f f e c t by v i r t u e of i t s s e n s i t i v i t y t o naloxone and the a b i l i t y t o d e v e l o p c r o s s -t o l e r a n c e w i t h c h r o n i c morphine t r e a t m e n t . Not o n l y have the e n d o r p h i n s been s t r o n g l y i m p i c a t e d i n the a n t i n o c i c e p t i v e e f f e c t s of these d i f f e r e n t s t r e s s o r s , but i t appears t h a t the B-endorphin and e n k e p h a l i n e r g i c systems have the c a p a c i t y t o be d i f f e r e n t i a l l y a c t i v a t e d . E l e c t r o a c u p u n c t u r e f o r example, appears t o i n v o l v e p i t u i t a r y B-endorphin (Cheng, Pomeranz, & Yu, 1979), a l t h o u g h the a n t i n o c i c e p t i v e e f f e c t s of abnormal motion l i k e l y i n v o l v e the e n k e p h a l i n systems. B u c k e t t (1979) has a l s o demonstrated a v e r y s h o r t d u r a t i o n a n t i n o c i c e p t i v e e f f e c t of f o o t s h o c k i n mice t h a t l i k e l y i n v o l v e s the e n k e p h a l i n s r a t h e r than the B-endorphin system. Nonopiate mechanisms• In c o n t r a s t t o the t y p e s of s t r e s s o r s mentioned above, t h e r e a r e a number of s t r e s s o r s t h a t produce a n a l g e s i a t h a t i s n e i t h e r a f f e c t e d by naloxone nor shows c r o s s - t o l e r a n c e w i t h morphine. For example, i t has been r e p o r t e d t h a t c o l d - w a t e r swimming (Bodnar, K e l l y , S t e i n e r , & Glusman, 1978), i n s u l i n a d m i n i s t r a t i o n (Bodnar, K e l l y , Mansour, & Glusman, 1979), 2-deoxy-D-glucose (2-DG) a d m i n i s t r a t i o n (Bodnar, K e l l y , & Glusman, 1979), f o o t s h o c k a d m i n i s t r a t i o n (Hayes, Bennet, Newlon, & Mayer, 1978), and c o n d i t i o n e d a n a l g e s i a (Chance & R o s e c r a n s , 1979a, 1979b) a c t through an endogenous p a i n m o d u l a t i n g system t h a t i s not o p i a t e i n n a t u r e . A l t h o u g h the p o s s i b l e mechanisms of n o n - o p i a t e SIA a r e f o r the most p a r t unknown, r e c e n t e v i d e n c e has suggested two p o s s i b l e nonopiate. p a i n m o d u l a t i n g mechanisms. V a s o p r e s s i n ( a n t i -186 d i u r e t i c hormone),is r e l e a s e d from the p i t u i t a r y and has r e c e n t l y been i m p l i c a t e d i n the SIA phenomenon. Rat s w i t h d i a b e t e s i n s i p i d u s , a c o n d i t i o n accompanied by v e r y low v a s o p r e s s i n l e v e l s , a re i n s e n s i t i v e t o the a n t i n o c i c e p t i v e e f f e c t s of c o l d - w a t e r swimming (Bodnar, Zimmerman, N i l a v e r , Mansour, Thomas, K e l l y , & Glusman, 1980). V a s o p r e s s i n has a l s o been found t o e x i s t i n the r a t b r a i n ( G l i c k & B r o w n s t e i n , 1980) and has a p o t e n t a n a l g e s i c a c t i o n when a d m i n i s t e r e d i n t r a c r a n i a l l y or s y s t e m i c a l l y ( B e r n t s o n & Berson, 1980). The v a s o p r e s s i n h y p o t h e s i s may e x p l a i n why hypophysectomy a t t e n u a t e s a n a l g e s i a i n d u c e d by c o l d - w a t e r swimming and 2-DG (Bodnar, Glusman, B r u t u s , S p i a g g i a , & K e l l y , 1979) w i t h o u t endogenous o p i a t e i n v o l v e m e n t . Dopamine (DA) has a l s o been i m p l i c a t e d i n the n o n - o p i a t e forms of SIA. Bodnar et a l . (1980) f o r example, have found t h a t apomorphine, a DA a g o n i s t , a t t e n u a t e s c o l d - w a t e r swim a n a l g e s i a . C o n s i s t e n t w i t h t h i s f i n d i n g , Crowley, R o d r i g u e z -S i e r r a , and Komisurak (1977) have found t h a t DA a g o n i s t s a t t e n u a t e , and DA a n t a g o n i s t s f a c i l i t a t e , a n t i n o c i c e p t i o n i n d u ced by v a g i n a l p r o b i n g i n r a t s . In c o n t r a s t , K u l k a r n i (1980) has suggested t h a t drugs t h a t i n h i b i t c a t e c h o l a m i n e f u n c t i o n such as a l p h a - m e t h y l - p a r a -t y r o s i n e , r e s e r p i n e , h a l o p e r i d o l , and c h l o r p r o m a z i n e w i l l a b o l i s h a n a l g e s i a induced by heat s t r e s s or i m m o b i l i z a t i o n . I t i s not known i f the d i f f e r e n t i a l i n v o l v e m e n t of c a t e c h o l a m i n e s i n t h e s e s t u d i e s r e f l e c t s a d i f e r e n t i a l i n v o l v e m e n t of c a t e c h o l a m i n e systems i n a n a l g e s i a induced by d i f f e r e n t s t r e s s o r s ( i . e . c o l d - w a t e r , h e a t , or i m m o b i l i z a t i o n ) or i s 187 merely the r e s u l t of p r o c e d u r a l d i f f e r e n c e s among the s t u d i e s . I t i s a l s o p o s s i b l e t h a t the drugs used were a c t i n g i n a d i f f e r e n t manner than i s n o r m a l l y assumed. Apomorphine f o r example, i s thought t o b i n d t o a t l e a s t some o p i a t e r e c e p t o r s i t e s but has l i t t l e a n a l g e s i c e f f e c t . J a f f e and M a r t i n (1975) i n d i c a t e t h a t the emetic a c t i o n s of apomorphine may be a b o l i s h e d by n a l o x o n e , an o p i a t e a n t a g o n i s t . I t s h o u l d be noted t h a t i t has been suggested t h a t f o o t s h o c k a c t i v a t e s b oth an o p i a t e and a n o n o p i a t e p a i n m o d u l a t i o n system. Even w i t h i n the same s t u d y , f o o t s h o c k has been shown t o produce n a l o x o n e - r e v e r s i b l e and n a l o x o n e -i n s e n s i t i v e a n t i n o c i c e p t i v e e f f e c t s ( L e w i s , Cannon, & L i e b e s k i n d , 1980). Three mins of c o n t i n u o u s f o o t s h o c k produced an a n t i n o c i c e p t i v e e f f e c t t h a t was not s e n s i t i v e t o n a l o x o n e ; whereas, 30 min of i n t e r m i t t e n t f o o t s h o c k produced an a n t i n o c i e p t i v e e f f e c t t h a t was a t t e n u a t e d by b o t h naloxone and dexamethasone t r e a t m e n t . The same s t r e s s o r t h e n , i s c a p a b l e of a c t i v a t i n g e i t h e r an o p i a t e or a n o n - o p i a t e p a i n m o d u l a t i n g system, depending on the a d m i n i s t r a t i o n p a r a m e t e r s . A l l of the s t r e s s o r s d i s c u s s e d above have not o n l y been a d m i n i s t e r e d i n d i f f e r e n t forms, but have w i d e l y d i f f e r e n t p h y s i c a l parameters a s s o c i a t e d w i t h them. C o l d - w a t e r swim s t r e s s f o r example, has much d i f f e r e n t p h y s i c a l and t e m p o r a l parameters than does f o o t s h o c k . I t i s p o s s i b l e t h a t the parameters of c o l d - w a t e r swim s t r e s s c o u l d be a d j u s t e d so as t o a c t i v a t e an o p i a t e - t y p e p a i n m o d u l a t i o n system. The p o s s i b i l i t y of e s c a p i n g the s t r e s s o r may a l s o be i m p o r t a n t i n the a c t i v a t i o n of an endogenous p a i n c o n t r o l system. J a c k s o n , M a i e r , and Coon (1980) 188 have r e c e n t l y demonstrated t h a t e s c a p a b l e v e r s u s i n e s c a p a b l e f o o t s h o c k produced d i f f e r e n t degrees of a n t i n o c i c e p t i o n . I t would seem from the above d i s c u s s i o n t h a t the term ' s t r e s s - i n d u c e d a n a l g e s i a ' i s somewhat of a misnomer i n t h a t ' s t r e s s ' does not n e c e s s a r i l y a c t i v a t e a s p e c i f i c p a i n m o d u l a t i o n system. In f a c t , some t r e a t m e n t s t h a t q u a l i f y as s t r e s s o r s produce no d e t e c t a b l e degree of a n t i - n o c i c e p t i o n (Hayes, Bennet, Newlon, & Mayer, 1978, W i l i e r , Boureau, & A l b e -F e s s a r d , 1979). Not o n l y may d i f f e r e n t t y p e s of s t r e s s o r s a c t i v a t e d i f f e r e n t p a i n m o d u l a t i o n systems, but the d u r a t i o n of the s t r e s s o r and the p e r c e i v e d a b i l i t y t o c o n t r o l the s t r e s s o r may d e t e r m i n e which type of system, i f any, i s a c t i v a t e d . The s i g n i f i c a n c e of th e s e m u l t i p l e systems and the reasons f o r the a p p a r e n t l y a r b i t r a r y manner i n which they a r e a c t i v a t e d ' i n response t o s t r e s s remains unknown. A p p l i c a t i o n s of the m o t i o n - i n d u c e d a n a l g e s i a phenomenon. I t i s p o s s i b l e t h a t abnormal motion may have some u s e f u l n e s s as a n o n p h a r m a c o l o g i c a l means of p a i n c o n t r o l i n humans and o t h e r a n i m a l s . The u s e f u l n e s s of t h i s p r o c e d u r e has been c l e a r l y demonstrated i n the p r e s e n t t h e s i s i f one i s concerned w i t h the a d m i n i s t r a t i o n of an ac u t e n o x i o u s s t i m u l u s t o l a b o r a t o r y a n i m a l s . A b r i e f p e r i o d of abnormal motion produces a l a r g e but s h o r t - l i v e d r e d u c t i o n i n t h e r e a c t i o n t o the n o x i o u s s t i m u l u s . The use of t h i s p r o c e d u r e s h o u l d be encouraged as i t m i n i m i z e s the trauma t o the a n i m a l g e n e r a t e d by a d m i n i s t r a t i o n of the n o x i o u s s t i m u l u s . I t a l s o f o l l o w s t h a t t h i s p r o c e d u r e s h o u l d not be used i f one i s i n t e r e s t e d i n e i t h e r the r e a c t i o n of the a n i m a l t o n o x i o u s s t i m u l i ( e.g. S t a u b l i & 189 Huston, 1979) or i n v a r i o u s b i o c h e m i c a l a s s a y s t h a t may be a f f e c t e d by the a c t i v a t i o n of an o p i a t e p e p t i d e system. In humans, n o n p h a r m a c o l o g i c a l means of p a i n m o d u l a t i o n o f f e r a number of p o t e n t i a l advantages over more c o n v e n t i o n a l p h a r m a c o l o g i c a l methods of p a i n c o n t r o l . F i r s t , they l i k e l y do not have the same a d d i c t i v e p o t e n t i a l or would be as s u s c e p t i b l e t o abuse as the o p i a t e and o p i a t e - d e r i v e d a n a l g e s i c drugs ( J a f f e & M a r t i n , 1975; Snyder, 1977). Second, n o n p h a r m a c o l o g i c a l p a i n c o n t r o l t e c h n i q u e s l i k e l y do not have the many u n d e s i r a b l e s i d e e f f e c t s of t y p i c a l a n a l g e s i c drugs (see J a f f e & M a r t i n , 1975). In a d d i t i o n t o the s e advantages, which a re common t o a l l n o n p h a r m a c o l o g i c a l means of p a i n m o d u l a t i o n , abnormal motion would seem t o have some unique advantages. I t i s easy t o a d m i n i s t e r , r e q u i r i n g o n l y a motion d e v i c e t o s t i m u l a t e the v e s t i b u l a r o r g a n s . The d e v i c e used t o s t i m u l a t e the v e s t i b u l a r system c o u l d be as s i m p l e as a r o t a t i n g c h a i r i n which the p a t i e n t c o u l d s i t and have h i s head moved r e p e a t e d l y out of the p l a n e of r o t a t i o n . T h i s t e c h n i q u e ( G r a y b i e l , Wood, M i l l e r , & Cramer, 1968; Cowings, B i l l i n g h a m , & Toscano, 1978) g e n e r a t e s ' c o r i o l i s a c c e l e r a t i o n s ' w i t h i n the s e m i - c i r c u l a r c a n a l s and can be of s u f f i c i e n t i n t e n s i t y t o induce motion s i c k n e s s . The e x p e r i e n c e of abnormal m o t i o n , a l t h o u g h p o s s i b l y not p l e a s a n t , i s p o s s i b l y not as n o x i o u s as some o t h e r t e c h n i q u e s c o u l d be (e.g . t r a n s - c u t a n e o u s e l e c t r i c a l s t i m u l a t i o n ) . There a r e few s i d e e f f e c t s of abnormal motion t h a t o u t l a s t the p e r i o d of s t i m u l a t i o n and even motion s i c k n e s s , s h o u l d i t d e v e l o p , can be c o n t r o l l e d by a d j u s t i n g the i n t e n s i t y of the s t i m u l u s so t h a t the u n p l e a s a n t e f f e c t s may be m i n i m i z e d (Reason & Brand, 1975). 190 At t h i s time however, e m p i r i c a l c o n f i r m a t i o n of an a n t i n o c i c e p t i v e e f f e c t of abnormal motion i n humans does not e x i s t . The a n t i n o c i c e p t i v e e f f e c t of abnormal m o t i o n , even i f i t does e x i s t i n humans, may be of somewhat l i m i t e d u s e f u l n e s s i n human p a i n c o n t r o l . Most p a i n of c l i n i c a l c o n c e r n i s r e a s o n a b l y l o n g l a s t i n g and a l l d e m o n s t r a t i o n s t o d a t e of the a n t i n o c i c e p t i v e e f f e c t of abnormal motion have c o n c e n t r a t e d on a r e d u c t i o n of r e s p o n s i v e n e s s t o a c u t e p a i n f u l s t i m u l i . T h i s a c u t e t e s t f o r a n t i n o c i c e p t i o n may r e v e a l n o t h i n g about the e f f e c t i v e n e s s of the abnormal-motion t r e a t m e n t i n p a i n s t a t e s of l o n g e r d u r a t i o n . A v e r y l a r g e p o r t i o n of the p a i n - c o n t r o l l i t e r a t u r e c o n c e r n s methods f o r a l l e v i a t i n g p a i n of r e l a t i v e l y l o n g d u r a t i o n , and i t would seem t h a t i f an a n t i n o c i c e p t i v e e f f e c t of abnormal motion i s t o be c l i n i c a l l y u s e f u l , i t must a l l e v i a t e p a i n of l o n g e r d u r a t i o n s than t h a t caused by exposure t o b r i e f s t i m u l i . Perhaps one way of c o n d u c t i n g t h i s e x a m i n a t i o n would be t o examine the e f f e c t of the abnormal motion t r e a t m e n t i n an a n i m a l model of " t o n i c " p a i n . Such a t e s t has r e c e n t l y been d e s c r i b e d by Dennis and M elzack (1979). T h i s t e s t appears t o p r o v i d e a p a i n s t i m u l u s of r e l a t i v e l y l o n g d u r a t i o n and hence c o u l d be used t o e v a l u a t e the l o n g - t e r m a n t i n o c i c e p t i v e e f f e c t s of abnormal mot i o n . I t may seem t h a t a c l i n i c a l l y u s e f u l r o l e f o r abnormal motion can be r e j e c t e d on the grounds t h a t the a n a l g e s i a produced i s of t o o s h o r t a d u r a t i o n t o be u s e f u l . T h i s i s not n e c e s s a r i l y the case however, and i t i s p o s s i b l e t h a t a c u t e 191 exposure t o abnormal motion would have some u s e f u l n e s s i n c h r o n i c p a i n c o n d i t i o n s . A l t h o u g h i t i s t r u e t h a t a c u t e non-p h a r m a c o l o g i c a l p a i n c o n t r o l t e c h n i q u e s (such as t r a n s c u t a n e o u s e l e c t r i c shock) produce b r i e f a n a l g e s i a i n normal a n i m a l s t e s t e d w i t h a c u t e p a i n f u l s t i m u l i (Hayes et a l . , 1978), i t i s a l s o t r u e t h a t t h e s e same t e c h n i q u e s can produce p r o l o n g e d p a i n r e l i e f l a s t i n g weeks i n humans (Melzack & D e n n i s , 1978; M e l z a c k , 1973). The p o s s i b l e u s e f u l n e s s of abnormal motion i n human c l i n i c a l p a i n syndromes t h e n , cannot be r e j e c t e d out of hand and abnormal motion may prove t o be a v a l u a b l e a d j u n c t t o o t h e r forms of p a i n c o n t r o l . MOTION SICKNESS E x p e r i m e n t s 13 and 14 of the p r e s e n t t h e s i s c o n f i r m e d p r e v i o u s r e p o r t s (Green & R a c h l i n , 1973, 1976; H a r o u t u n i a n & R i c c i o , 1975) i n d i c a t i n g t h a t abnormal motion can a c t as the u n c o n d i t i o n e d s t i m u l u s i n the c o n d i t i o n e d t a s t e a v e r s i o n paradigm. Attempts t o r e v e r s e the development of the c o n d i t i o n e d t a s t e a v e r s i o n i n r a t s p r e t r e a t e d w i t h two d i f f e r e n t o p i a t e a n t a g o n i s t s f a i l e d . The f a i l u r e t o r e v e r s e or b l o c k the development of a c o n d i t i o n e d t a s t e d a v e r s i o n i n response t o motion by the use of o p i a t e a n t a g o n i s t s was i n t e r p r e t e d t o suggest t h a t endogenous o p i a t e p e p t i d e s r e l e a s e d i n response t o abnormal motion have no e a s i l y d i s c e r n i b l e r o l e i n the development of the c o n d i t i o n e d t a s t e a v e r s i o n . I t i s a l s o p o s s i b l e however, t h a t o p i a t e p e p t i d e s may a c t on r e c e p t o r mechanisms t h a t a r e i n s e n s i t i v e t o naloxone or n a l t r e x o n e . Cheng and Pomeranz (1980) f o r example, have shown t h a t a c u p u n c t u r e a n a l g e s i a i s mediated by one t ype of o p i a t e 192 r e c e p t o r ( n a l o x o n e - s e n s i t i v e ) and suggest t h a t o t h e r b e h a v i o u r a l e f f e c t s of o p i a t e p e p t i d e s may be mediated by a n o t h e r ( n a l o x o n e -i n s e n s i t i v e ) t ype of r e c e p t o r (see a l s o L o r d , W a t e r f i e l d , Hughes, & K o s t e r l i t z , 1976; Ward, M e t c a l f , & Rees, 1978, f o r f u r t h e r d i s c u s s i o n of m u l t i p l e o p i a t e r e c e p t o r s ) . T h i s p o s s i b i l i t y seems u n l i k e l y as an e x p l a n a t i o n f o r the p r e s e n t r e s u l t s as the nausea, v o m i t i n g , and t a s t e a v e r s i o n - i n d u c i n g p r o p e r t i e s of morphine can be b l o c k e d or a t t e n u a t e d by naloxone ( J a f f e & M a r t i n , 1975; Le B l a n c & C a p p e l l , 1 9 7 5 ; van der Kooy & P h i l l i p s , 1977). One d i f f i c u l t y a s s o c i a t e d w i t h a p p l y i n g the r e s u l t s of the p r e s e n t e x p e r i m e n t s t o the mechanisms of motion s i c k n e s s i s t h a t the c o n d i t i o n e d t a s t e a v e r s i o n paradigm has never been a p p r o p r i a t e l y v a l i d a t e d as a model of motion s i c k n e s s i n the r a t . That i s , a l t h o u g h i t i s perhaps i n t u i t i v e l y a t t r a c t i v e t o view the r a t s as b e i n g made ' s i c k ' by the motion and hence d e v e l o p i n g an a v e r s i o n t o a n o v e l f l u i d , t h i s c o n n e c t i o n has y e t t o be v e r i f i e d . In f a c t , some e v i d e n c e e x i s t s t h a t s u g g e s t s t h a t the m o t i o n - i n d u c e d t a s t e a v e r s i o n i n r a t s i s not d i r e c t l y a nalogous t o the motion s i c k n e s s found i n o t h e r a n i m a l s p e c i e s . L e s i o n s of t h e a r e a postrema have been found t o e l i m i n a t e motion s i c k n e s s i n p r i m a t e s ( B r i z z e e , Ordy, & M e h l e r , 1980a, 1980b) and dogs (Money, 1970) and a l s o e l i m i n a t e t a s t e a v e r s i o n s produced by c e n t r a l l y a c t i n g emetic drugs ( C o i l & G a r c i a , 1977; H a r t l e y , 1977). T h i s f a c t s u g g e s t s t h a t both motion s i c k n e s s and c e n t r a l l y a c t i n g emetic drugs e x e r t t h e i r nauseogenic and emetic a c t i o n s t h r o u g h the a r e a postrema. In r a t s however, a r e a postrema l e s i o n s have been found t o e l i m i n a t e t a s t e a v e r s i o n s 193 i n d u ced by c e n t r a l l y a c t i n g emetic drugs but not a v e r s i o n s produced by abnormal motion ( H a r t l e y , 1977). T h i s may i n d i c a t e t h a t the mechanisms by which abnormal motion and c e n t r a l l y a c t i n g e metic drugs e x e r t t h e i r e f f e c t s i n r a t s a r e d i f f e r e n t than i n o t h e r s p e c i e s . I f t h i s were t r u e , then i t would be u n l i k e l y t h a t s t u d y i n g the mechanisms of m o t i o n - i n d u c e d t a s t e a v e r s i o n s i n the r a t would r e v e a l any mechanisms of motion s i c k n e s s t h a t would have c r o s s - s p e c i e s g e n e r a l i t y . However, i t s h o u l d be noted t h a t the H a r t l e y (1977) r e s u l t s appeared o n l y i n a b s t r a c t form and e v a l u a t i o n of the s e r e s u l t s was thus i m p o s s i b l e . These c r i t i c i s m s do not however, d i s c o u n t the p o s s i b l e u s e f u l n e s s of the c o n d i t i o n e d t a s t e a v e r s i o n paradigm and i n f o r m a t i o n d e r i v e d from the study of the n e u r a l mechanisms of c o n d i t i o n e d t a s t e a v e r s i o n s i n the stu d y of the p h y s i o l o g i c a l mechanisms of motion s i c k n e s s . M o t i o n f o r example, produces both motion s i c k n e s s ( v o m i t i n g ) and c o n d i t i o n e d t a s t e a v e r s i o n s i n the s q u i r r e l monkey (Ordy & B r i z z e e , 1980; Roy & B r i z z e e , 1979) . In s p e c i e s o t h e r than the r a t , a r e a postrema l e s i o n s e l i m i n a t e b oth the motion s i c k n e s s ( B r i z z e e , Ordy, & M e h l e r , 1980) and i l l n e s s produced by c e n t r a l l y a c t i n g emetic drugs ( C o i l & G a r c i a , 1977; Wang & B o r i s o n , 1952) t h a t a r e c a p a b l e of i n d u c i n g c o n d i t i o n e d t a s t e a v e r s i o n s . These f a c t s suggest t h a t u n c o n d i t i o n e d s t i m u l i f o r t a s t e a v e r s i o n s and motion s i c k n e s s may share s i m i l a r n e u r a l mechanisms. A d d i t i o n a l e v i d e n c e f o r t h i s s h a r ed mechanism i s p r o v i d e d by the f a c t t h a t doses of emetic drugs not n o r m a l l y e f f e c t i v e i n p r o d u c i n g v o m i t i n g w i l l summate w i t h a s u b - e f f e c t i v e motion s t i m u l u s t o produce v o m i t i n g 194 (Money, 1970). Braveman (1975) has f u r t h e r suggested t h a t motion and a v a r i e t y of o t h e r i l l n e s s - i n d u e i n g agents (morphine, l i t h i u m c h l o r i d e , e t c . ) w i l l d e v e l o p c r o s s - t o l e r a n c e i n the c o n d i t i o n e d t a s t e a v e r s i o n paradigm. P r i o r exposure t o morphine or l i t h i u m c h l o r i d e f o r example, i n h i b i t s the f o r m a t i o n of subsequent t a s t e a v e r s i o n s when motion i s used as the u n c o n d i t i o n e d s t i m u l u s . T h i s c r o s s - t o l e r a n c e e f f e c t i n the f o r m a t i o n of c o n d i t i o n e d t a s t e a v e r s i o n s has a l s o been demonstrated w i t h a v a r i e t y of o t h e r p h a r m a c o l o g i c a l t r e a t m e n t s (e.g. Brown, Amit, Smith, & Rockman, 1979; Gamzu, 1975). Triesman (1977) has h y p o t h e s i z e d t h a t not o n l y a r e the mechanisms of motion s i c k n e s s and drug induced i l l n e s s s i m i l a r , they may be i d e n t i c a l . I f i t i s t r u e t h a t motion s i c k n e s s and c o n d i t i o n e d t a s t e a v e r s i o n s produced by c e n t r a l l y a c t i n g emetic drugs share common n e u r a l mechanisms, t h e r e a r e a t l e a s t two i m p o r t a n t i m p l i c a t i o n s of t h i s r e l a t i o n s h i p . F i r s t , a'daptation t o emesis produced by r e p e a t e d exposure t o c e n t r a l l y a c t i n g emetic drugs s h o u l d produce c r o s s - t o l e r a n c e t o the i l l n e s s - i n d u c i n g p r o p e r t i e s of motion . T h i s means t h a t p r o t e c t i v e a d a p t a t i o n t o motion s i c k n e s s c o u l d be a c q u i r e d by r e p e a t e d exposures t o emetic d r u g s . At p r e s e n t , p r o t e c t i v e a d a p t a t i o n t o motion s i c k n e s s o c c u r s o n l y when the organism i s r e p e a t e d l y exposed t o the motion p r e v i o u s l y used t o induce the motion s i c k n e s s (Reason & Brand, 1975). I f the c e n t r a l e metic mechanism c o u l d be adapted t o the i l l n e s s - i n d u c i n g p r o p e r t i e s of c e n t r a l l y a c t i n g emetic d r u g s , t h i s a d a p t a t i o n s h o u l d e x t e n d t o a l l i l l n e s s - i n d u c i n g t r e a t m e n t s t h a t share the same mechanisms. 195 The p o s s i b l e commonality between the a c t i o n s of c e n t r a l l y a c t i n g e m e t i c drugs and motion s i c k n e s s may a l s o e x p l a i n the a c t i o n s of drugs e f f e c t i v e i n p r e v e n t i n g r e l a t i v e l y m i l d forms of motion s i c k n e s s . These d r u g s , which i n c l u d e some p h e n o t h i a z i n e s , some a n t i h i s t a m i n e s , and some a n t i c h o l i n e r g i c s , do not seem t o e x e r t t h e i r a n t i m o t i o n - s i c k n e s s e f f e c t s t h r o u g h any one n e u r o c h e m i c a l system (Reason & Brand, 1975; Wood, 1979). That i s , not a l l p h e n o t h i a z i n e s , a n t i h i s t a m i n e s , or a n t i c h o l i n e r g i c s a r e e f f e c t i v e i n p r e v e n t i n g motion s i c k n e s s . These drugs must a l s o be taken w e l l b e f o r e exposure t o motion (Wood, 1979) and a l l have nausea and v o m i t i n g as s i d e e f f e c t s a t h i g h d o s e s . I t i s p o s s i b l e t h a t t h e s e drugs p r e v e n t motion s i c k n e s s i n a manner t h a t i s s i m i l a r t o Braveman's f i n d i n g (1975) t h a t p r e e x p o s u r e t o morphine or o t h e r drugs p r e v e n t s the f o r m a t i o n of a m o t i o n - i n d u c e d t a s t e a v e r s i o n . P reexposure t o drugs t h a t a r e a b l e t o b l o c k or weakly s t i m u l a t e the c e n t r a l emetic mechanisms may i n h i b i t the subsequent a c t i v a t i o n of t h e s e mechanisms by a n o t h e r s t i m u l u s such as abnormal m o t i o n . I t would seem t h e n , t h a t the t a s t e a v e r s i o n paradigm, a l t h o u g h i t may not be a s u i t a b l e a ssay of motion s i c k n e s s i n the r a t , may prove u s e f u l i n the i n v e s t i g a t i o n of the p h y s i o l o g i c a l b a s i s of motion s i c k n e s s . CALMING EFFECTS OF ABNORMAL MOTION The p r e s e n t t h e s i s i n c l u d e s an experiment d e s c r i b i n g a p o s s i b l e c a l m i n g or a n x i o l y t i c e f f e c t of abnormal m o t i o n . R a t s t h a t had been exposed t o a b r i e f p e r i o d of abnormal motion s u b s e q u e n t l y demonstrated an i n h i b i t i o n of a s p e c i e s - t y p i c a l response t o n o v e l or a v e r s i v e s t i m u l i . T h i s s p e c i e s t y p i c a l 196 res p o n s e , d e f e n s i v e b u r y i n g , has r e c e n t l y been shown t o be a f f e c t e d by a n x i o l y t i c drugs i n the same f a s h i o n t h a t the response i s a f f e c t e d by abnormal motion ( P i n e l & T r e i t , i n p r e s s , 1981). Treatment w i t h the a n x i o l y t i c agents diazepam or c h l o r d i a z e p o x i d e suppress b u r y i n g i n r a t s i n much the same manner as a b r i e f p e r i o d of abnormal mot i o n . T h i s p u t a t i v e c a l m i n g or a n x i o l y t i c e f f e c t i s i n complete a c c o r d w i t h p r e v i o u s s t u d i e s s u g g e s t i n g a c a l m i n g e f f e c t of abnormal v e s t i b u l a r s t i m u l a t i o n i n both humans (Korner & Thoman, 1972; Ter V r u g t & Pederson, 1973; Reason & Brand, 1975; Weeks, 1979) and o t h e r s p e c i e s (Thoman & K o r n e r , 1971; S t a u b l i & Huston, 1979). In a d d i t i o n , i t i s i n agreement w i t h a n a e c d o t a l e v i d e n c e c o n c e r n i n g the c a l m i n g e f f e c t s of r o c k i n g c h a i r s , s w i n g i n g or swaying m o t i o n s , and the l i k e (Weeks, 1979). The d e f e n s i v e b u r y i n g paradigm would seem u s e f u l f o r f u r t h e r e x p l o r a t i o n of t h i s a n x i o l y t i c e f f e c t f o r a v a r i e t y of r e a s o n s . F i r s t , the response i s r e l i a b l y e l i c i t e d by a v a r i e t y of n o v e l s t i m u l i ( T e r l e c k i , P i n e l , & T r e i t , 1979) and by p r e v i o u s l y n e u t r a l s t i m u l i t h a t have been p a i r e d w i t h an a v e r s i v e s t i m u l u s such as an e l e c t r i c shock ( P i n e l & T r e i t , 1978). Second, the response i t s e l f i s h i g h l y s t e r e o t y p e d and e a s i l y o b s e r v e d by even u n t r a i n e d o b s e r v e r s ( c f . P i n e l & T r e i t , i n p r e s s , 1981). T h i r d , t h e r e i s a d i r e c t and r e l i a b l e r e l a t i o n s h i p between the amount of b u r y i n g e x h i b i t e d by a s u b j e c t and the i n t e n s i t y of the a v e r s i v e s t i m u l u s ( T r e i t , P i n e l , & T e r l e c k i , 1980) and thus the amount of b u r y i n g b e h a v i o u r o b s e r v e d i s p r o b a b l y r e l a t e d t o the a v e r s i v e n e s s of the s t i m u l u s o b j e c t . F o u r t h , T r e i t ( P i n e l & T r e i t , i n p r e s s , 197 1981) has shown t h a t by u s i n g d i f f e r e n t s t i m u l u s i n t e n s i t i e s i n the c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm, i t i s p o s s i b l e t o e l i m i n a t e n o n - s p e c i f i c e f f e c t s of the p u t a t i v e a n x i o l y t i c t r e a t m e n t as e x p l a n a t i o n s f o r the s u p p r e s s i o n of b u r y i n g . Diazepam, f o r example, s u p p r e s s e s d e f e n s i v e b u r y i n g i n the u n c o n d i t i o n e d b u r y i n g paradigm and a t low shock i n t e n s i t i e s i n the c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm. Diazepam i n the same dose however, has l i t t l e e f f e c t on d e f e n s i v e b u r y i n g b e h a v i o u r when h i g h shock i n t e n s i t i e s a r e used i n the c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm. The f a c t t h a t diazepam f a i l s t o a f f e c t d e f e n s i v e b u r y i n g a t h i g h shock i n t e n s i t i e s e l i m i n a t e s n o n - s p e c i f i c drug a c t i o n s such as motor d e b i l i t a t i o n or a n a l g e s i a as p l a u s i b l e a l t e r n a t e e x p l a n a t i o n s f o r the s u p p r e s s i o n e f f e c t a t low shock i n t e n s i t i e s and i n the u n c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm. In o r d e r f o r the p u t a t i v e a n x i o l y t i c e f f e c t of abnormal motion t o be c o n s i d e r e d a v a l i d ' a n x i o l y t i c ' e f f e c t r a t h e r than the p r o d u c t of some n o n - s p e c i f i c motor d e b i l i t a t i o n or i l l n e s s e f f e c t , the T r e i t (1981) p r o c e d u r e u s i n g d i f f e r e n t shock i n t e n s i t i e s can be used. To d a t e , t h i s experiment has not been co n d u c t e d . In a d d i t i o n t o meeting the c r i t e r i a t h a t T r e i t and P i n e l ( i n p r e s s , 1981) have e s t a b l i s h e d f o r a n x i o l y t i c a g ents i n the d e f e n s i v e b u r y i n g paradigm, i t i s a l s o n e c e s s a r y t o examine the e f f e c t s of- abnormal motion i n o t h e r b e h a v i o u r a l t e s t s d e s i g n e d t o s c r e e n a n x i o l y t i c a g e n t s . These t e s t s i n c l u d e c o n f l i c t t e s t s , open f i e l d e x p l o r a t i o n , locomotor a c t i v i t y i n s i t u a t i o n s where locomotor a c t i v i t y i s p u n i s h e d by f o o t s h o c k , and o t h e r s (Corey, 1978; G l i c k , 1976). 198 Should an a n x i o l y t i c a c t i o n of abnormal motion be c o n f i r m e d , i t w i l l p o s s i b l y be the f i r s t d e m o n s t r a t i o n of the a c t i v a t i o n of an endogenous ' a n x i o l y t i c ' mechanism. The e x i s t e n c e of such a system i s suggested by the presence of endogenous b e n z o d i a z e p i n e r e c e p t o r s i n the c e n t r a l nervous system ( T a l l m a n , P a u l , S k o l n i k , & G a l l a g e r , 1980). Because the r e c e p t o r s e x i s t , i t seems l o g i c a l t o assume t h a t t h e r e a r e endogenous b e n z o d i a z e p i n e - 1 i k e m o l e c u l e s t h a t a c t i v a t e t h e s e r e c e p t o r s i n response t o the a p p r o p r i a t e e n v i r o n m e n t a l s t i m u l i . A l t h o u g h i t i s t e m p t i n g t o s p e c u l a t e on the u s e f u l n e s s of a non-p h a r m a c o l o g i c a l a n x i o l y t i c mechanism t h a t c o u l d be a c t i v a t e d a t w i l l w i t h o u t the adver s e e f f e c t s a t t e n d a n t t o drug use, i t must f i r s t be demonstrated t h a t the p u t a t i v e a n x i o l y t i c e f f e c t of abnormal motion i s more than a p o s s i b l e s i d e e f f e c t of abnormal motion such as i l l n e s s . In c o n j u n c t i o n w i t h t h i s however, i t i s i n t e r e s t i n g t o note t h a t r e c e n t e v i d e n c e i n d i c a t e s t h a t l i t h i u m may e x e r t i t s a n t i - a g g r e s s i v e e f f e c t s i n r a t s t h r o u g h the a r e a postrema, an a r e a thought t o p r i m a r i l y d e t e c t the presence of i l l n e s s - i n d u c i n g t o x i n s such as l i t h i u m c h l o r i d e ( H a r t l e y , 1977). I f the a r e a postrema i s l e s i o n e d i n r a t s , the a n t i -a g g r e s s i v e e f f e c t s of l i t h i u m a r e a b o l i s h e d (McGlone, R i t t e r , & K e l l y , 1980). CONCLUSIONS The e x p e r i m e n t s c o n t a i n e d i n t h i s t h e s i s have demonstrated t h r e e main b e h a v i o u r a l e f f e c t s of abnormal motion i n the r a t : a n t i n o c i c e p t i o n , the f o r m a t i o n of a c o n d i t i o n e d t a s t e a v e r s i o n , and a p o s s i b l e a n x i o l y t i c e f f e c t . Are t h e s e b e h a v i o u r a l e f f e c t s d i s t i n c t i n t h a t they r e p r e s e n t the b e h a v i o u r a l m a n i f e s t a t i o n s 199 of d i f f e r e n t p h y s i o l o g i c a l mechanisms or do they r e p r e s e n t the b e h a v i o u r a l e f f e c t s of a common u n d e r l y i n g mechanism i n d i f f e r e n t t a s k s ? I t has been suggested i n v a r i o u s p l a c e s throughout t h i s t h e s i s t h a t endogenous o p i a t e p e p t i d e s may be the common mechanisms u n d e r l y i n g the b e h a v i o u r a l e f f e c t s of abnormal m o t i o n . A l t h o u g h the a c t i v a t i o n of an endogenous p e p t i d e system appears t o mediate the a n t i n o c i c e p t i v e e f f e c t of abnormal motion (and p o s s i b l y the a n x i o l y t i c e f f e c t ) , t h i s a c t i v a t i o n does not appear t o be r e s p o n s i b l e f o r the t a s t e a v e r s i o n - i n d u c i n g p r o p e r t i e s of abnormal m o t i o n . I t i s a l s o p o s s i b l e t h a t abnormal motion e x e r t s i t b e h a v i o u r a l e f f e c t s t h r o u g h a g e n e r a l s t r e s s mechanism. A l t h o u g h a g e n e r a l s t r e s s mechanism may e x p l a i n the t a s t e a v e r s i o n d a t a and poss i . b l y the a n t i n o c i c e p t i v e e f f e c t , i t does not e x p l a i n the a n x i o l y t i c e f f e c t found i n Experiment 15. In Experiment 15, i t was found t h a t exposure t o abnormal m o t i o n , a s t r e s s o r , s u p p r e s s e d performance of a d e f e n s i v e response whereas exposure t o a d i f f e r e n t s t r e s s o r , e l e c t r i c shock, s l i g h t l y f a c i l i t a t e d performance of the response. T h i s d i s s o c i a t i o n would seem t o render the s t r e s s h y p o t h e s i s u n l i k e l y . I t would seem t h e n , t h a t the b e h a v i o u r a l e f f e c t s of abnormal motion may r e p r e s e n t the a c t i v a t i o n of a number of hormonal or n e u r o c h e m i c a l systems. The p r e s e n t t h e s i s has demonstrated t h a t the v e s t i b u l a r system may p l a y an i m p o r t a n t r o l e i n b e h a v i o u r . Abnormal a c t i v a t i o n of t h i s system r e s u l t s not o n l y i n m o t i o n - i n d u c e d i l l n e s s , but a l s o i n the a c t i v a t i o n of an endogenous p a i n 200 m o d u l a t i n g system, and a p o s s i b l e endogenous a n x i o l y t i c mechanism. V e s t i b u l a r s t i m u l a t i o n t h e n , may have a much g r e a t e r i n v o l v e m e n t i n b e h a v i o u r than has been p r e v i o u s l y assumed and i t i s hoped t h a t the e x p e r i m e n t s p r e s e n t e d here w i l l s t i m u l a t e f u r t h e r r e s e a r c h i n the almost u n e x p l o r e d area of the v e s t i b u l a r system and i t s r o l e i n b e h a v i o u r . 201 REFERENCES A d l e r , M.W. O p i o i d p e p t i d e s . L i f e S c i e n c e s , 1980, 26(7), 497-510. A k i l , H., Madden, J.,. P a t r i c k , R.L., & B a r c h a s , J.P. 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