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Pavlovian conditioning and tolerance to analgesia produced by electrical stimulation in the brainstem Paul, Dennis John 1983

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PAVLOVIAN CONDITIONING AND TOLERANCE TO ANALGESIA PRODUCED BY ELECTRICAL STIMULATION IN THE BRAINSTEM by DENNIS JOHN PAUL B. A. , U n i v e r s i t y o f C i n c i n n a t i / 1980 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS i n THE FACULTY OF GRADUATE STUDIES (Department of Psychology) We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA November, 19S3 © Dennis John P a u l , 1983 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree a t the U n i v e r s i t y o f B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and study. I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the head o f my department o r by h i s o r her r e p r e s e n t a t i v e s . I t i s understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date DE-6 (3/81) i i ABSTRACT P a v l o v i a n C o n d i t i o n i n g and T o l e r a n c e t o A n a l g e s i a Produced by E l e c t r i c a l S t i m u l a t i o n i n the Bra ins tem by Dennis John P a u l S t i m u l a t i o n o f the p e r i a q u e d u c t a l gray (PAG) o f the m i d b r a i n produces an a n a l g e s i a t h a t resembles o p i a t e a n a l g e s i a . There i s c o n s i d e r a b l e b e h a v i o r a l ) p h a r m a c o l o g i c a l and p h y s i o l o g i c a l e v i d e n c e to sugges t a common u n d e r l y i n g mechanism f o r s t i m u l a t i o n produced a n a l g e s i a (SPA) and o p i a t e a n a l g e s i a . T o l e r a n c e to the a n a l g e s i c e f f e c t o f o p i a t e drugs has been shown t o be s u b j e c t t o the laws o f c l a s s i c a l c o n d i t i o n i n g . S p e c i f i c a l l y , c e r t a i n a s p e c t s of t o l e r a n c e t o o p i a t e s have been r e l a t e d t o a compensatory p h y s i o l o g i c a l r e s p o n s e e l i c i t e d by cues t h a t r e l i a b l y p r e d i c t the drug e f f e c t . G iven the apparent s i m i l a r i t y between SPA and o p i a t e a n a l g e s i a / the p r e s e n t exper iments t e s t the h y p o t h e s i s t h a t t o l e r a n c e t o SPA i s a l s o s u b j e c t t o the laws o f c l a s s i c a l c o n d i t i o n i n g and show a compensatory p h y s i o l o g i c a l response. Exper iment 1 sought t o determine i f t o l e r a n c e t o SPA can be e x t i n g u i s h e d . E l e c t r i c a l s t i m u l a t i o n o f the PAG was d e l i v e r e d f o r 5 min per day i n the p r e s e n c e o f d i s t i n c t i v e e n v i r o n m e n t a l cues. B r a i n - s t i m u l a t i o n i n c r e a s e d t a i l - f l i c k l a t e n c i e s / and t o l e r a n c e deve loped over seven d a i l y s e s s i o n s . H a l f o f the r a t s i i i were then g i v e n 1 2 e x t i n c t i o n t r i a l s which c o n s i s t e d o f exposure t o the e n v i r o n m e n t a l cues, w i thout b r a i n - s t i m u l a t i o n . The rema in ing s u b j e c t s s t a y e d i n t h e i r home cages throughout t h i s p e r i o d . When t e s t e d a g a i n w i t h b r a i n - s t i m u l a t i o n i n the e x p e r i m e n t a l e n v i r o n m e n t , a n i m a l s i n the e x t i n c t i o n group d i s p l a y e d s i g n i f i c a n t SPA. The home cage group remained t o l e r a n t t o the PAG s t i m u l a t i o n . R e a q u i s i t i o n o f t o l e r a n c e was observed i n the e x t i n c t i o n group. Exper iment 2 was d e s i g n e d t o determine i f t o l e r a n c e to SPA i s c o n t e x t s p e c i f i c . H a l f o f the an ima ls were s t i m u l a t e d i n a d i s t i n c t i v e e x p e r i m e n t a l environment . The r e m a i n i n g a n i m a l s were s t i m u l a t e d i n t h e i r c o l o n y room. S t i m u l a t i o n o f the PAG produced s t r o n g a n a l g e s i a , w i th t o l e r a n c e d e v e l o p i n g over seven d a i l y s e s s i o n s . On t e s t days a l l an ima ls were s t i m u l a t e d i n the c o l o n y room. Animals t h a t deve loped t o l e r a n c e i n the e x p e r i m e n t a l environment showed s i g n i f i c a n t a n a l g e s i a when s t i m u l a t e d i n the c o l o n y room. Animals g i v e n an e i g h t h c o n s e c u t i v e s t i m u l a t i o n s e s s i o n i n the c o l o n y room remained t o l e r a n t t o the s t i m u l a t i o n . Exper iment 3 examined the h y p o t h e s i s t h a t t o l e r a n c e t o SPA s h o u l d be accompanied by the development o f a h y p e r a l g e s i c response to e n v i r o n m e n t a l cues. PAG s t i m u l a t i o n produced s t r o n g a n a l g e s i a wi th complete t o l e r a n c e d e v e l o p i n g over seven d a i l y s e s s i o n s . A n o n s t i m u l a t e d c o n t r o l group was g i v e n d a i l y t a i l - f l i c k t e s t s and showed a s l i g h t l y i n c r e a s i n g t r e n d i n l a t e n c i e s . On the t e s t day h a l f o f the s t i m u l a t e d an ima ls were t e s t e d wi thout b r a i n - s t i m u l a t i o n and a h y p e r a l g e s i c response was observed . The r e m a i n i n g s t i m u l a t e d r a t s r e c e i v e d an a d d i t i o n a l i v stimulation session and did not show a decreased t a i l - F l i c k latency. These r e s u l t s extend the generality of the conditioning model of tolerance to the tolerance that develops to SPA. The SPA paradigm may prove to be a valuable t o o l for examining physiological substrates of conditioned tolerance. Dr. Anthony G. P h i l l i p s V CONTENTS INTRODUCTION 1 T h e o r i e s o f Drug T o l e r a n c e . 1 S t i m u l a t i o n Produced A n a l g e s i a 14 R a t i o n a l e 22 EXPERIMENT 1: EXTINCTION OF TOLERANCE TO STIMULATION PRODUCED ANALGESIA 25 Method 26 R e s u l t s 29 D i s c u s s i o n 34 EXPERIMENT 2: CONTEXT SPECIFICITY OF TOLERANCE TO STIMULATION PRODUCED ANALGESIA 37 Method 39 R e s u l t s 40 D i s c u s s i o n 45 EXPERIMENT 3: HYPERALGESIC CONDITIONAL RESPONSE FROM PERIAQUEDUCTAL GRAY STIMULATION TOLERANT RATS 48 Method 49 R e s u l t s 50 D i s c u s s i o n 55 GENERAL DISCUSSION 58 v i REFERENCES 69 v i i LIST OF FIGURES F i g u r e 1. Afferent pathways i n v o l v e d i n n o c i c e p t i o n and e f f e r e n t pathways i n v o l v e d i n modu la t ion o f p a i n p e r c e p t i o n . 1 6 F i g u r e 2. E l e c t r o d e p lacements o f r a t s i n the EXTINCTION group and CONTROL group from Exper iment 1 30 F i g u r e 3. Mean t a i l - f l i c k l a t e n c i e s i n seconds f o r the EXTINCTION and CONTROL groups i n Exper iment i 32 F i g u r e 4. E l e c t r o d e p lacements o f r a t s i n the ENVIRONMENT DIFFERENT group and ENVIRONMENT SAME group from Exper iment 2. . . 41 F i g u r e 5. Mean t a i l - f l i c k l a t e n c i e s i n seconds f o r the ENVIRONMENT DIFFERENT and ENVIRONMENT SAME groups i n Exper iment 2 43 F i g u r e 6. E l e c t r o d e p lacements of r a t s i n the HYPERALGESIA group. S-CONTROL group and i m p l a n t e d NS-CONTROL group an ima ls from Exper iment 3 51 F i g u r e 7. Mean t a i l - f l i c k l a t e n c i e s i n seconds f o r the HYPERALGESIA, s t i m u l a t e d c o n t r o l (S-CONTROL), and v i i i nonstimulated control (NS-CONTROL) groups i n Experiment 3 53 Figure 8. Possible locations of the "integrator. " r e l a t i v e to the PAG 63 i x ACKNOWLEDGEMENTS I am i n d e b t e d t o Dr. Anthony P h i l l i p s f o r h i s s u p p o r t throughout the e x e c u t i o n o f t h e s e exper iments , and f o r h i s i n s i g h t f u l c r i t i c i s m s throughout the p r e p a r a t i o n o f t h i s manuscr ip t . I am a l s o g r a t e f u l t o Dr. Donald W i l k i e and Dr. Rober t MacMahon f o r t h e i r c r i t i i s m , which c o n t r i b u t e d t o the f i n a l form o f t h i s manuscr ip t . I would a l s o l i k e t o thank F r e d e r i c k LeP iane and L u c i l l e Hoover f o r t h e i r t o l e r a n c e ( a l s o c o n d i t i o n e d ) . T h i s r e s e a r c h was s u p p o r t e d by the N a t i o n a l Research C o u n c i l o f Canada gran t (67-7808) t o Dr. P h i l l i p s . 1 INTRODUCTION Drug t o l e r a n c e may be d e f i n e d as a d e c r e a s e i n the p h a r m a c o l o g i c a l e f f e c t o f a g i v e n dose o f a drug a f t e r s u c c e s s i v e a d m i n i s t r a t i o n s , o r t o the need f o r p r o g r e s s i v e l y l a r g e r doses o f a drug t o produce the same e f f e c t s on s u c c e s s i v e a d m i n i s t r a t i o n s . The u s e f u l n e s s o f a p a r t i c u l a r p h a r m a c o l o g i c a l agent i s o f t e n l i m i t e d by i t s r e l a t i v e a b i l i t y t o deve lop t o l e r a n c e . C o n c u r r e n t w i th the development o f t o l e r a n c e i s development o f the r e l a t e d phenomenon o f dependence. Dependence r e f e r s t o an a l t e r e d b i o l o g i c a l s t a t e which r e q u i r e s r e p e a t e d a d m i n i s t r a t i o n o f a drug i n o r d e r t o a v o i d a c h a r a c t e r i s t i c symptom complex known as a b s t a i n a n c e syndrome. There i s some c o n t r o v e r s y s u r r o u n d i n g the i s s u e o f whether t o l e r a n c e and dependance are m a n i f e s t a t i o n s o f the same phenomenon. C l e a r l y , the e f f i c a c y o f a drug as a t h e r a p e u t i c t o o l s h o u l d not i n c l u d e p e r p e t u a l dosage i n c r e a s e s . An u n d e r s t a n d i n g o f the d e t e r m i n a n t s o f t o l e r a n c e c o u l d l e a d t o more e f f e c t i v e p h a r m a c o l o g i c a l t rea tment regimens as w e l l as i n c r e a s i n g our knowlege o f n e u r a l mechanisms o f drug a c t i o n . T h e o r i e s of Drug T o l e r a n c e D e s p i t e decades o f i n t e n s e r e s e a r c h t h e r e i s l i t t l e agreement on the p o s s i b l e mechanisms o f drug t o l e r a n c e . T h e o r i e s o f t o l e r a n c e may be r o u g h l y d i v i d e d i n t o two c a t e g o r i e s : p h y s i o l o g i c a l t h e o r i e s and b e h a v i o r a l t h e o r i e s ( S i e g e l , 1975). The f i r s t ca tegory , s t r e s s e s the d i r e c t a c t i o n of the drug on the b i o l o g i c a l system. S p e c i f i c a l l y , t h i s c a t e g o r y c o n t a i n s t h e o r i e s t h a t account f o r t o l e r a n c e th rough a mechanism t h a t changes the 2 r e a c t i o n of the r e c e p t o r t o the drug, or r e s t r i c t s access of the drug to the receptor. T h i s view sees the b i n d i n g of the drug to the r e c e p t o r as the c r i t i c a l event. I t i g n o r e s the f a c t t h a t the e f f e c t of the molecule-receptor i n t e r a c t i o n i s superimposed on the normal a c t i v i t y of the nervous system, a system d e f i n e d by i t s p l a s t i c i t y . However, i n these t h e o r i e s the nervous system i s t r e a t e d as a constant. The second category, the l e a r n i n g t h e o r i e s , c o n t a i n s model systems t h a t s t r e s s the p l a s t i c i t y of the nervous system i n i t s r e a c t i o n t o the drug-receptor i n t e r a c t i o n . These t h e o r i e s emphasize the importance of l e a r n e d a s s o c i a t i o n s to t o l e r a n c e development. Although l e a r n i n g t h e o r i e s of t o l e r a n c e s t r e s s the system on which the a c t i o n of the drug i s superimposed, they do not exclude the p o s s i b i l i t y of an important i n t e r a c t i o n with the r e c e p t o r complex. Despite the divergence of p o s t u l a t e d mechanisms, there i s g e n e r a l agreement on those phenomena t h a t should be e x p l a i n e d by a v a l i d theory of t o l e r a n c e (Hug, 1972). The c r i t i c a l c h a r a c t e r i s t i c s are l i s t e d below. Tolerance Development. Measurable t o l e r a n c e can be seen with as l i t t l e as one a d m i n i s t r a t i o n of morphine (Kornetsky & Bain, 1968). A f t e r g r a d u a l dosage increments, s u b j e c t s have been known to t o l e r a t e doses hundreds of times the o r i g i n a l LD-50 (Seevers & Deneau, 1963; Seevers & Woods, 1953). Cross Tolerance. S u b j e c t s t o l e r a n t to one drug are t o l e r a n t to p h a r m a c o l o g i c a l l y s i m i l a r agents. O c c a s i o n a l l y , s u b j e c t s may be c r o s s t o l e r a n t to d i s s i m i l a r drugs with s i m i l a r 3 p h a r m a c o l o g i c a l e f f e c t s . P e r s i s t a n c e o f T o l e r a n c e . T o l e r a n c e to morphine has been shown t o l a s t up t o one year w i thout i n t e r v e n i n g a d m i n i s t r a t i o n s (Coch in & Kornetsky . 1964; K o r n e t s k y & Ba in , 1968). T h e o r i e s d e s i g n e d t o e x p l a i n one o f these c h a r a c t e r i s t i c s tend t o have t r o u b l e w i th the o t h e r s . A v a l i d t h e o r y must e x p l a i n a l l o f t h e s e phenomena. P h y s i o l o g i c a l T h e o r i e s A l though a l l p h y s i o l o g i c a l t h e o r i e s o f t o l e r a n c e cannot be l i s t e d here, a few are d e s c r i b e d t o g i v e the r e a d e r a f e e l i n g f o r the ca tegory . M e t a b o l i c T h e o r i e s . T h e o r i e s o f t o l e r a n c e c l a s s i f i e d as m e t a b o l i c t h e o r i e s contend t h a t the r e l e v a n t e f f e c t o f the drug i s t o i n c r e a s e the r a t e a t which the drug i s e l i m i n a t e d from the system, t h e r e b y r e d u c i n g a v a i l a b i l i t y o f the drug t o b i n d t o r e c e p t o r s . M e t a b o l i c change i s s u p p o r t e d by d i f f e r e n c e s i n d i s t r i b u t i o n o f r a d i o a c t i v e l y l a b e l e d morphine w i t h i n the CNS o f t o l e r a n t and n o n t o l e r a n t dogs and r a t s (Mule, 1965; Mule, Redman & F l e s h e r , 1967; Mule & Woods, 1962; Mule, Woods & M e l l e t t , 1962). However, t h e s e a u t h o r s p o i n t out t h a t the magnitude o f d i f f e r e n c e s seen a r e not s u f f i c i e n t t o e x p l a i n t o l e r a n c e . Immunologica l theory . C o c h i n and K o r n e t s k y (1964) have proposed t h a t t o l e r a n c e resembles an immune phenomenon, w i th the drug as an a n t i g e n . T h i s theory was c o n c e i v e d t o e x p l a i n the l o n g - l a s t i n g n a t u r e o f t o l e r a n c e . Serum and t i s s u e p a s s i v e transfer exper iments , i n which e x t r a c t s from t o l e r a n t a n i m a l s a re i n j e c t e d i n t o n o n t o l e r a n t an ima ls , have been i n c o n c l u s i v e , w i th 4 some s t u d i e s r e p o r t i n g a d e c r e a s e i n s e n s i t i v i t y t o morphine (Ungar & Cohen, 1966; Tulunay, K i r a n & Kaymakcalan, 1970) w h i l e o t h e r s r e p o r t no change (Smith & Takemori , 1968) or an i n c r e a s e i n s e n s i t i v i t y (Korne tsky & K i p l i n g e r , 1963; K i p l i n g e r & C l i f t , 1964). At p r e s e n t we can o n l y s p e c u l a t e on the r o l e an immune r e a c t i o n may p l a y i n the i n d u c t i o n o f t o l e r a n c e . Receptor M o d i f i c a t i o n T h e o r i e s . S e v e r a l t h e o r i e s o f drug t o l e r a n c e propose t h a t the r e l e v a n t a c t i o n o f the drug i s t o change the number, s t r u c t u r e or s e n s i t i v i t y o f the r e c e p t o r s . C o l l i e r (1965), f o r example, contends t h a t drug e x p e r i e n c e i n d u c e s the f o r m a t i o n o f " s i l e n t r e c e p t o r s " . The drug w i l l then b i n d to t h e s e r e c e p t o r s , l e a v i n g l e s s o f the drug t o b i n d t o " p h a r m a c o l o g i c a l " r e c e p t o r s . B i n d i n g s t u d i e s employ ing r a d i o a c t i v e l i g a n d s have shown an i n c r e a s e i n number o f b i n d i n g s i t e s w i th drug e x p e r i e n c e . However, a n t a g o n i s t s a l s o i n c r e a s e the number o f r e c e p t o r s a t much lower doses (Per t , P a s t e r n a c & Snyder, 1973) but, o f c o u r s e , do not i n d u c e t o l e r a n c e . A more r e c e n t t h e o r y p roposes t h a t the b i n d i n g o f the drug molecu le to the r e c e p t o r causes a s t r u c t u r a l change i n the r e c e p t o r (Tulunay & Takemori , 1974; Snyder & Mat thysse , 1975 pp. 65-67) . The e f f e c t o f t h i s change i s t o i n c r e a s e the a f f i n i t y o f the r e c e p t o r t o as ye t u n i s o l a t e d endogenous drug a n t a g o n i s t s . Tulunay & Takemori base t h e i r t h e o r y on s h i f t s i n pA2, a r e p u t e d compar ison o f a f f i n i t y betweeen an a g o n i s t and a n t a g o n i s t , a f t e r exposure to morphine. In v i v o , the d e f i n i t i o n of pA2 i s the n e g a t i v e l o g a r i t h m o f the molar dose o f the i n j e c t e d a n t a g o n i s t t h a t reduces the e f f e c t o f a double dose ( i . e. 2 x ED-50) to t h a t 5 o f a s i n g l e i n c e r e b r o s p i n a l f l u i d o f r a t s , but t h i s subs tance has ye t t o be i s o l a t e d . The use of the pA2 method f o r t h e o r e t i c a l f o r m u l a t i o n u n d e r l i n e s the f l aw i n p h y s i o l o g i c a l t h e o r i e s o f t o l e r a n c e . A c r i t i c a l , i m p l i c i t assumpt ion o f the method, as i t i s a p p l i e d i n v i v o , i s t h a t a l l change t a k e s p l a c e a t the a g o n i s t r e c e p t o r super imposed on a s t a t i c system. Aga in , t h e r e i s no a p r i o r i b a s i s f o r t h i s assumpt ion. L e a r n i n g T h e o r i e s o f T o l e r a n c e . The i d e a t h a t l e a r n i n g may p l a y an i m p o r t a n t r o l e i n the development o f drug dependence has e x i s t e d f o r decades. Himmelsbach (1943) f i r s t sugges ted t h a t dependence i s c o n d i t i o n e d and s e t d i s s o c i a t i o n o f reward from a n a l g e s i a and e u p h o r i a as a r e s e a r c h g o a l . W i k l e r and h i s a s s o c i a t e s f a v o r e d a l e a r n i n g theory o f dependence i n t r y i n g t o e x p l a i n many c l i n i c a l o b s e r v a t i o n s , such as h i g h r e l a p s e r a t e s and o c c u r r e n c e o f a b s t a i n a n c e symptoms months a f t e r d e t o x i f i c a t i o n (Wik ler , 1963, 1965, 1972, 1977; W i k l e r & Pescor , 1967; W i k l e r , P e s c o r , M i l l e r & N o r e l l , 1971). These t h e o r e t i c i a n s viewed dependence and t o l e r a n c e as s e p a r a t e but r e l a t e d phenomena. When they are seen as m a n i f e s t a t i o n s o f the same phenomenon the e x t e n s i o n t o a r o l e f o r l e a r n i n g i n the development o f t o l e r a n c e i s d i r e c t . C o n s i d e r a b l e i n d i r e c t e v i d e n c e shows a p a r a l l e l between l e a r n i n g and development o f t o l e r a n c e . E l e c t r o c o n v u l s i v e shock (Kesner, P r i a n o & DeWitt, 1976; S to le rman, Bunker, Johnson, J a r v i k , K r i v o y & Zimmerman, 1976), 6-hydroxydopamine l e s i o n s (Ayhan, 1972; B l a s i g , Herz & Gramsch, 1975), and a d m i n i s t r a t i o n o f p r o t e i n s y n t h e s i s i n h i b i t o r s (Cohen, Keats , K r i v o y & Ungar, 6 1965; Cox & G i n s b e r g . 1969; Cox & Osman. 1970; L e B l a n c . Matsunga & K a l a t . 1976) have a l l been shown t o r e t a r d t o l e r a n c e as w e l l as v a r i o u s l e a r n i n g t a s k s . Three prominent t h e o r i e s have c l a i m e d a r o l e f o r l e a r n i n g i n drug t o l e r a n c e . B e h a v i o r a l T o l e r a n c e . Dews (1962) proposed t h a t many o f the d e b i l i t a t i n g e f f e c t s of a drug c o u l d be c o u n t e r a c t e d by o p e r a n t l y c o n d i t i o n e d b e h a v i o r a l p a t t e r n s . In operant c o n d i t i o n i n g , per formance o f a r e s p o n s e l e a d s t o r e i n f o r c e m e n t o r punishment, thereby i n c r e a s i n g or d e c r e a s i n g the l i k e l i h o o d t h a t the r e s p o n s e w i l l be per formed a g a i n (Mack intosh. 1974). In t h i s i n s t a n c e , the observed r e d u c t i o n i n drug e f f e c t i s seen as a consequence o f d i f f e r e n t i a l r e i n f o r c e m e n t o f more e f f e c t i v e p a t t e r n s o f behav io r . Dews g i v e s as an example the s lowed speech and widened g a i t o f the c h r o n i c a l c o h o l i c as compensat ing f o r the motor e f f e c t s o f a l c o h o l . E x p e r i m e n t a l l y , t h i s phenomenon i s seen as an improvement i n per formance o f e t h a n o l - i n t o x i c a t e d r a t s on a t r e a d m i l l , o n l y when the an ima ls a r e a l l o w e d t o run w h i l e i n t o x i c a t e d . A c o n t r o l group, which ran b e f o r e i n t o x i c a t i o n , showed l e s s or no t o l e r a n c e to the e t h a n o l on subsequent t e s t s (Wenger, T i f f a n y , Bombardier , N i c h o l l s & Woods, 1981; Ka lan t , LeBlanc & G i b b i n s , 1976). Dews c a l l e d t h i s b e h a v i o r a l compensat ion " b e h a v i o r a l t o l e r a n c e " . Because t o l e r a n c e i s c o n t i n g e n t upon per formance of the task , t h i s phenomenon has come t o be known as c o n t i n g e n t t o l e r a n c e . T h i s t h e o r y seems t o account f o r improved per formance on some w e l l - i n t e g r a t e d motor t a s k s , but cannot be an e x p l a n a t i o n o f t o l e r a n c e t o p h y s i o l o g i c a l e f f e c t s , such as t a c h y c a r d i a and 7 hypothermia/ o r t o a n a l g e s i a as measured by s p i n a l l y mediated r e f l e x e s , o r p s y c h o l o g i c a l e f f e c t s such as d r u g - i n d u c e d euphor ia . B e h a v i o r a l l y Augmented T o l e r a n c e . In a m o d i f i c a t i o n o f t h i s theory , L e B l a n c and h i s c o - w o r k e r s (LeBlanc , K a l a n t & G i b b i n s , 1973) have combined p h y s i o l o g i c a l t h e o r i e s w i t h c o n t i n g e n t t o l e r a n c e . They proposed t h a t the f u n c t i o n o f l e a r n i n g i n t o l e r a n c e development i s t o a c c e l e r a t e a q u i s i t i o n . As e v i d e n c e , L e B l a n c et. a l . (1973) showed i n the t r e a d m i l l paradigm t h a t s u b j e c t s p e r f o r m i n g the task w h i l e i n t o x i c a t e d a q u i r e d t o l e r a n c e f a s t e r than c o n t r o l s , but the u l t i m a t e degree o f t o l e r a n c e t o the motor e f f e c t s o f e t h a n o l i s i d e n t i c a l f o r both the e x p e r i m e n t a l and c o n t r o l s u b j e c t s . They c o n c l u d e d t h a t per formance o f a b e h a v i o r may i n f l u e n c e the r a t e o f a d a p t a t i o n t o a drug, but not the e x t e n t o f a d a p t a t i o n , and r e f e r e d t o t h i s phenomenon as b e h a v i o r a l l y augmented t o l e r a n c e . C o n d i t i o n i n g Model o f T o l e r a n c e . R e c e n t l y , a t t e n t i o n has f o c u s s e d on the r o l e t h a t c l a s s i c a l c o n d i t i o n i n g may p l a y i n the development o f t o l e r a n c e t o c e r t a i n drug e f f e c t s . In the c l a s s i c a l c o n d i t i o n i n g exper iment , s t i m u l i a r e p r e s e n t e d t o the organism w i thout r e g a r d t o i t s behav io r . A c o n t i n g e n c y i s s e t up so t h a t one s t i m u l u s ( c o n d i t i o n a l s t i m u l u s , CS) r e l i a b l y p r e d i c t s the o c c u r e n c e of the second s t i m u l u s ( u n c o n d i t i o n a l s t i m u l u s , UCS). The UCS i s s e l e c t e d because i t e l i c i t s a r e l e v a n t response , termed the u n c o n d i t i o n a l r e s p o n s e (UCR). In P a v l o v ' s (1927) famous exper iments , meat pas te UCS was chosen because i t r e l i a b l y e l i c i t e d s a l i v a t i o n , the UCR. P a v l o v ' s b e l l CS does not e l i c i t s a l i v a t i o n , p r i o r to p a i r i n g w i th the UCR. The CS comes 8 t o e l i c i t the response , now termed the c o n d i t i o n a l r e s p o n s e (CR), as a f u n c t i o n o f the CS-UCS p a i r i n g . To complete the example, a f t e r s e v e r a l p a i r i n g s o f the b e l l CS and meat p a s t e UCS the b e l l , by i t s e l f , w i l l now e l i c i t s a l i v a t i o n . S i e g e l (1975) has proposed t h a t n a r c o t i c t o l e r a n c e i s the r e s u l t o f l e a r n i n g an a s s o c i a t i o n between the s y s t e m i c e f f e c t s o f the drug and e n v i r o n m e n t a l cues t h a t r e l i a b l y p recede these s y s t e m i c e f f e c t s . In S i e g e l ' s o r i g i n a l model, the drug i s d e s i g n a t e d as the UCS, the e f f e c t s o f the drug a re the UCR, the e n v i r o n m e n t a l cues a r e the CS, and a homeosta t ic compensatory mechanism, o p p o s i t e i n d i r e c t i o n t o the UCR, i s the CR. T h i s homeosta t ic CR summates w i th the e f f e c t o f the drug t o c o u n t e r a c t i t s e f f e c t . T h i s reduced drug e f f e c t i s , by d e f i n i t i o n , t o l e r a n c e . A r e c e n t i n t e r p r e t a t i o n , which b r i n g s t h i s theory i n l i n e w i th t r a d i t i o n a l P a v l o v i a n t h e o r y , d i f f e r e n t i a t e s between drugs t h a t a c t on e f f e r e n t and a f f e r e n t arms o f the nervous system. Drugs t h a t produce t o l e r a n c e a r e seen as a c t i n g on the e f f e r e n t arm of a system wi th n e g a t i v e feedback. S i n c e the d i r e c t e f f e c t o f the drug would not be p r o c e s s e d by the c e n t r a l nervous system, the drug cannot be a s t i m u l u s . In t h i s case , the drug e f f e c t would be the UCS wi th the o r g a n i s m ' s h o m e o s t a t i c r e a c t i o n to t h i s s t i m u l u s as the UCR (E ike lboom & Stewart , 1982). The e n v i r o n m e n t a l cues and the h o m e o s t a t i c compensatory mechanism remain as the CS and CR, r e s p e c t i v e l y . As the e n v i r o n m e n t a l cues are p a i r e d c o n s i s t e n t l y w i th the drug e f f e c t , the cues g a i n the a b i l i t y t o e l i c i t the compensatory mechanism to c o u n t e r a c t the 9 expec ted drug e f f e c t . Morphine i s c o n s i d e r e d to be the p r o t o t y p e drug i n t o l e r a n c e s t u d i e s , p r i m a r i l y because o f i t s c l i n i c a l r e l e v a n c e (Seevers & Deneaui 1963). Pr imary s u p p o r t f o r t h i s P a v l o v i a n model comes from exper iments employ ing the a n a l g e s i c e f f e c t o f morphine as a dependent measure. Three l i n e s o f d i r e c t e v i d e n c e suggest t h a t P a v l o v i a n c o n d i t i o n i n g may account f o r a t l e a s t some i n s t a n c e s o f t o l e r a n c e . The f i r s t l i n e o f e v i d e n c e i s the demonst ra t ion t h a t c o n d i t i o n e d e n v i r o n m e n t a l cues p r e s e n t e d w i th a s a l i n e p lacebo can e l i c i t the homeosta t i c compensatory mechanism. In o t h e r words, f a l l o w i n g p a i r i n g s , the CS by i t s e l f e l i c i t s the CR. With morphine t o l e r a n t r a t s t h i s i s seen as a h y p e r a l g e s i c response a f t e r p r e s e n t a t i o n o f c o n d i t i o n a l e n v i r o n m e n t a l cues ( S i e g e l , 1975). A l though a c o n d i t i o n a l compensatory response has a l s o been shown f o r the hypothermic e f f e c t o f a l c o h o l , i . e. hyper thermia , ( C r o w e l l , H inson & S i e g e l , 1981, Le, Pou los & C a p p e l l , 1979; M a n s f i e l d & Cunningham, 1980), S i e g e l ' s d e m o n s t r a t i o n w i th morphine has not been r e p l i c a t e d o u t s i d e h i s l a b o r a t o r y ( T i f f a n y , P e t r i e , Baker & Dahl , 1983). The second l i n e o f e v i d e n c e i s the d e m o n s t r a t i o n o f con tex t s p e c i f i c i t y o f morphine t o l e r a n c e . An ima ls made t o l e r a n t to the a n a l g e s i c e f f e c t o f morphine g i v e a r e l a t i v e l y n o n t o l e r a n t response when t e s t e d i n a d i s t i n c t environment . In o t h e r words, t h e r e i s a g e n e r a l i z a t i o n decrement between the t r a i n i n g CS and the d i s s i m i l a r t e s t CS (Advokat, 1980; S i e g e l , 1975, 1976). Contex t s p e c i f i c i t y o f t o l e r a n c e has a l s o been shown f o r morphine 10 i n d u c e d h y p e r a c t i v i t y (Mucha, V o l k o v s k i s & K a l a n t , 1981) and f o r e t h a n o l ' s hypothermic e f f e c t ( C r o w e l l e t a l . » 1981, Le e t a l . , 1979). A t h i r d l i n e o f exper iments demonstrate t h a t P a v l o v i a n p r o c e d u r e s which n o r m a l l y r e t a r d a q u i s i t i o n or ma in ta inance o f the CR a l s o r e t a r d the a q u i s i t i o n o r ma in ta inance of t o l e r a n c e . S p e c i f i c a l l y , u n p a i r e d p r e s e n t a t i o n o f the CS p r i o r t o ( l a t e n t i n h i b i t i o n ) , o r i n t e r m i t t e n t w i th ( p a r t i a l r e i n f o r c e m e n t ) CS-UCS p a i r i n g s w i l l s i g n i f i c a n t l y a t t e n u a t e the r a t e a t which t o l e r a n c e i s a q u i r e d ( S i e g e l , 1977). In a d d i t o n an e x p l i c i t u n p a i r i n g o f the CS and UCS, t h a t i s , p r e s e n t i n g both the CS and UCS, but never t o g e t h e r , p r i o r t o CS-UCS p a i r i n g , r e t a r d s t o l e r a n c e a q u i s i t i o n to a g r e a t e r e x t e n t than a l a t e n t i n h i b i t i o n p rocedure ( S i e g e l , 1981). S e v e r a l p r e s e n t a t i o n s o f the e n v i r o n m e n t a l CS wi thout a subsequent a n a l g e s i c UCS w i l l a t t e n u a t e an e s t a b l i s h e d t o l e r a n c e . In o t h e r words, t o l e r a n c e t o m o r p h i n e ' s a n a l g e s i c e f f e c t can be e x t i n g u i s h e d ( S i e g e l , 1975, 1976). An ima ls not r e c e i v i n g t h e s e e x t i n c t i o n t r i a l s over the same t ime p e r i o d remain t o l e r a n t to the morphine. T h i s e x t i n c t i o n e f f e c t has a l s o been demonstrated f o r amphetamine i n d u c e d a n o r e x i a (Poulos , W i l k i n s o n & C a p p e l l , 1981) and f o r e t h a n o l ' s hypothermic e f f e c t ( C r o w e l l e t a l . , 1981). T h e o r i e s t h a t c o n s i d e r o n l y the i n t e r a c t i o n o f the drug m o l e c u l e w i th the r e c e p t o r are i n s u f f i c i e n t t o e x p l a i n the i n f l u e n c e t h a t the e n v i r o n m e n t a l cues seem to have upon t o l e r a n c e . P h y s i o l o g i c a l t h e o r i e s o f t o l e r a n c e would p r e d i c t t h a t e q u a l exposure to the p h a r m a c o l o g i c a l agent s h o u l d produce e q u a l l e v e l s o f t o l e r a n c e . The c o n d i t i o n i n g 11 theory o f t o l e r a n c e , on the o t h e r hand, v iews the a s s o c i a t i o n o f p r e d i c t i v e cues w i th the drug e f f e c t s as a c r i t i c a l event. O b v i o u s l y , i f P a v l o v i a n p r o c e s s e s are a t p l a y i n the development o f t o l e r a n c e . then the "background" a c t i v i t y as w e l l as the a c t i v i t y a t the r e c e p t o r must be taken i n t o c o n s i d e r a t i o n i n any v a l i d t h e o r y o f t o l e r a n c e development. The c o n d i t i o n i n g t h e o r y o f t o l e r a n c e e a s i l y e x p l a i n s the c h a r a c t e r i s t i c s o f t o l e r a n c e when o t h e r t h e o r i e s f a i l . Because l e a r n i n g r e p r e s e n t s a r e l a t i v e l y permanent change, p e r s i s t a n c e o f t o l e r a n c e i s expected. A d m i n i s t r a t i o n o f d i v e r s e agents may be accompanied by s i m i l a r cues (eg. i d e n t i c a l a d m i n i s t r a t i o n p r o c e d u r e s ) . The homeosta t i c CR e l i c i t e d by these cues i n t o l e r a n t s u b j e c t s would c o u n t e r a c t drugs t h a t may o p e r a t e through a d i f f e r e n t mechanism, but have s i m i l a r e f f e c t s ( i . e. c r o s s t o l e r a n c e ) . Because t o l e r a n c e development seems t o f o l l o w a l e a r n i n g curve , r a t e of development i s e a s i l y e x p l a i n e d (Ka lant . Pou los & C a p p e l l , 1978; S i e g e l , i n p r e s s ) . There are , however, s e v e r a l phenomena t h a t a s s o c i a t i v e t h e o r i e s o f t o l e r a n c e have y e t to e x p l a i n . F i r s t , t o l e r a n c e has been demonstra ted i n an i l l e u m e x i s e d from m o r p h i n e - t o l e r a n t gu inea p i g s (Herz, Z i e g l g a n s b e r g e r , S c h u l z , F r y & Satoh, 1976). C l e a r l y , e n v i r o n m e n t a l i n f l u e n c e s on t h i s p r e p a r a t i o n s h o u l d be minimal . Second, l e a r n i n g t h e o r i e s have d i f f i c u l t y e x p l a i n i n g the t o l e r a n c e o f neonates born to d r u g - t o l e r a n t mothers ( S i e g e l , 1978; i n p r e s s ) . With the v a r i e t y o f modes of a c t i o n o f drugs and numerous e f f e c t s of any p a r t i c u l a r drug, i t i s q u i t e l i k e l y t h a t no mechanism of drug t o l e r a n c e i s u b i q u i t o u s . Separa te mechanisms, 12 both a s s o c i a t i v e and n o n a s s o c i a t i v e , may be r e s p o n s i b l e f o r d i f f e r e n t drug e f f e c t s ( S i e g e l . i n p r e s s ) . In a d d i t i o n , m u l t i p l e mechanisms may s y n e r g i i e t o produce the observed t o l e r a n c e to any one e f f e c t (LeBlanc et. a l . , 1973). Recent advances i n h i s t o l o g i c a l and p h y s i o l o g i c a l t e c h n i q u e s a r e now b e i n g a p p l i e d t o the s t u d y o f p h y s i o l o g i c a l mechanisms o f drug t o l e r a n c e . However. paradigms used thus f a r have proved i n s u f f i c i e n t f o r s t u d y i n g the p h y s i o l o g i c a l s u b s t r a t e s of c o n d i t i o n e d t o l e r a n c e (Advokat, 1980). I t would be of b e n e f i t t o e x p l o r e the s u b s t r a t e s o f each o f the r e p u t e d mechanisms. PROBLEMS WITH MULTIPLE EFFECTS OF DRUGS. I n t e r p r e t a t i o n o f p h a r m a c o l o g i c a l exper iments i n g e n e r a l and t o l e r a n c e s t u d i e s i n p a r t i c u l a r has been n o t o r i o u s l y d i f f i c u l t , and t h i s i s due p r i m a r i l y t o the m u l t i p l e e f f e c t s o f most drugs (Dews, 1962). P e r i p h e r a l a d m i n i s t r a t i o n o f morphine i n humans, f o r example, a f f e c t s r e s p i r a t o r y and p u l s e r a t e , v a s c u l a t u r e d i l a t i o n , g a s t r o i n t e s t i n a l m o t i l i t y , hormonal f u n c t i o n , f a t i g u e , and a c t i v i t y l e v e l , as w e l l as h a v i n g an a n a l g e s i c e f f e c t ( I s b e l l & White, 1953). I n t e r a c t i o n o f t h e s e many e f f e c t s o f morphine makes i t d i f f i c u l t t o f o c u s on a p a r t i c u l a r dependent measure. D i s t r i b u t i o n o f o p i o i d r e c e p t o r s i n the c e n t r a l nervous system and p e r i p h e r a l systems i s as v a r i e d as the e f f e c t s o f o p i a t e l i g a n d s . I n - v i t r o r a d i o l a b l e d b i n d i n g and a u t o r a d i o g r a p h i c t e c h n i q u e s (Atweh & Kuhar, 1977a, 1977b, 1977c; Pearson, B r a n d e i s , Simon & H i l l e r , 1980; P e r t , Kuhar & Snyder, 1976) have l o c a t e d o p i o i d r e c e p t o r s i n s p e c i f i c l o c i from the o l f a c t o r y b u l b s t o the s p i n a l cord . Atweh and Kuhar (1983) have 13 c o r r e l a t e d the d i s t r i b u t i o n o f o p i o i d r e c e p t o r s i n the b r a i n and s p i n a l c o r d w i th the m u l t i p l e e f f e c t s o f o p i a t e a d m i n i s t r a t i o n . F o r example, m i c r o i n j e c t i o n o f morphine i n t o the s t r i a t u m p r o d u c e s the muscular r i g i d i t y t h a t h i g h doses o f morphine a re known t o produce. But s t i l l , o v e r l a p e x i s t s : The a n a l g e s i c e f f e c t o f morphine i s i n f l u e n c e d by o p i o i d r e c e p t o r s i n the d o r s a l horn o f the s p i n a l c o r d , s u b s t a n t i a g e l a t i n o s a of the t r i g e m i n a l nerve , med ia l t h a l a m i c n u c l e i , i n t r a t h a l a m i c n u c l e i and p e r i a q u e d u c t a l gray matter. As p o i n t e d out by Dole and h i s c o l l e g u e s , the s tudy of t o l e r a n c e to o p i a t e s poses a p a r t i c u l a r l y p e r p l e x i n g problem as many o f the m u l t i p l e r e s p o n s e s t o the drug a r e d i f f i c u l t to measure i n an i s o l a t e d system (Snyder & Mat thysse , 1975 pp. 65-67) . Wi thout an i s o l a t e d system a l l r e s u l t s must be i n t e r p r e t e d w i t h i n the c o n t e x t o f p o s s i b l e i n t e r a c t i o n o f m u l t i p l e e f f e c t s . Two s o l u t i o n s t o t h i s problem a r e ev iden t . One method o f i s o l a t i n g an e f f e c t i s through l o c a l i n t r a c r a n i a l m i c r o i n j e c t i o n o f the l i g a n d . The e f f e c t o f t h i s p rocedure i s t o a l l o w o n l y a s p e c i f i c r e c e p t o r f i e l d a c c e s s t o the drug. S i n c e s p e c i f i c l o c i a r e c o r r e l a t e d wi th s p e c i f i c a c t i o n s o f o p i a t e s , the i n j e c t i o n w i l l a f f e c t a l i m i t e d number o f systems, t h e r e b y l i m i t i n g the e f f e c t s o f the drug. However, the m u l t i p l e i n j e c t i o n s needed f o r t o l e r a n c e r e s e a r c h a r e known t o produce t i s s u e damage at the i n j e c t i o n s i t e . A p i l o t s tudy u s i n g t h i s method proved d i f f i c u l t t o i n t e r p r e t due t o t h i s damage (Pau l & MacCrea, u n p u b l i s h e d da ta ) . An at tempt t o e x t i n g u i s h a c o n d i t i o n e d t o l e r a n c e to i n t r a c r a n i a l m i c r o i n j e c t i o n o f morphine 14 i n t o the PAG, r e s u l t e d i n a n o n s i g n i f i c a n t t r e n d towards s u c c e s s f u l e x t i n c t i o n . I t was f e l t t h a t the damage caused by the r e p e a t e d i n j e c t i o n s had l e s i o n e d the d e s c e n d i n g i n h i b i t o r y mechanismi making i t i m p a s s i b l e t o reproduce the p r o f o u n d e f f e c t seen w i th p e r i p h e r a l i n j e c t i o n s . T h i s p r o c e d u r e i s now b e i n g r e f i n e d by MacCrea and S i e g e l ( p e r s o n a l communicat ion! 1982). A second p o s s i b i l i t y i n v o l v e s 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 o f the neurons i n v o l v e d i n the drug mediated e f f e c t . S t i m u l a t i o n Produced A n a l g e s i a E l e c t r i c a l s t i m u l a t i o n o f the p e r i a q u e d u c t a l gray (PAG) i n the m i d b r a i n o f r a t , (Mayer, W o l f l e , A k i l , C a r d e r & L i e b e s k i n d , 1971; Reynolds , 1969), c a t ( L i e b e s k i n d , G u i l b a u d , Besson & O l i v e r a s , 1973), monkey (Goodman & Holcombe, 1975; Ruda, Hayes, Dubner & P r i c e , 1976), and man (Hosobuchi , Adam & L i n c h i t z , 1978; Hosobuchi , R o s s i e r , Bloom & G u i l l e m i n 1979; R i c h a r d s o n & A k i l , 1977) has been shown t o produce s i g n i f i c a n t l e v e l s of a n a l g e s i a . Mayer and h i s c o l l e g u e s (Mayer & L i e b e s k i n d , 1974; Mayer & P r i c e 1976; Watkins & Mayer, 1982) have c l a i m e d t h a t t h e r e i s s u f f i c i e n t e v i d e n c e t o propose a common s u b s t r a t e f o r s t i m u l a t i o n produced a n a l g e s i a (SPA) and morphine a n a l g e s i a . In o r d e r t o f a c i l i t a t e the r e l a t i o n o f SPA to morphine a n a l g e s i a , a b r i e f overv iew of the anatomy o f the c e n t r a l systems i n v o l v e d i n p a i n p e r c e p t i o n and o p i o i d a n a l g e s i a w i l l be g iven . A s c e n d i n g Pathways. S p i n o t h a l a m i c t r a c t . The s p i n o t h a l a m i c t r a c t has been r e c o g n i s e d as a pr imary pathway o f n o c i c e p t i v e i n f o r m a t i o n f o r 15 o v e r a c e n t u r y ( W i l l i s , 1976). Neurons o f t h i s t r a c t a r i s e from the d o r s a l horn of the s p i n a l c o r d ( G i e s l e r , Menetrey, G u i l b a u d & Bessorii 1976), and, a f t e r c r o s s i n g t o the c o n t r a l a t e r a l c o r d , c o u r s e through the a n t e r o l a t e r a l quadrant o f the s p i n a l whi te mat ter (F ig . 1) . S t u d i e s based on a n t e r o g r a d e l a b e l i n g w i th h o r s e r a d i s h p e r o x i d a s e have shown t h e s e neurons t o p r o j e c t t o the v e n t r o b a s a l , med ia l , and p o s t e r i o r tha lamus ( G i e s l e r , Basbaum & Menetrey, 1977). L e s i o n s anywhere a l o n g the c o u r s e of the s p i n o t h a l a m i c t r a c t may r e s u l t i n d e f i c i t s i n p a i n p e r c e p t i o n c o n t r a l a t e r a l and p o s t e r i o r t o the l e s i o n ( C a s s i n a r i & Pagni , 1969; Noordenbos i & W a l l , 1976; S p i l l e r & M a r t i n , 1921) S p i n o r e t i c u l a r Pathway. R e c e n t l y a g r e a t d e a l o f a t t e n t i o n has been g i v e n to an i m p o r t a n t a l t e r n a t i v e pathway f o r n o c i c e p t i v e i n f o r m a t i o n : the s p i n o r e t i c u l a r system. L i k e the s p i n o t h a l a m i c t r a c t , neurons o f t h i s pathway a r i s e i n the d o r s a l horn, c r o s s , and ascend i n the a n t e r o l a t e r a l f u n n i c u l i . However, t h e s e neurons p r o j e c t t o v a r i o u s m i d b r a i n s t r u c t u r e s , p a r t i c u l a r l y the tectum and the PAG (cf . F i e l d s & Basbaum, 1978). Because these b r a i n l o c i have p r o j e c t i o n s to the l i m b i c system, i t has been h y p o t h e s i z e d t h a t the s p i n o r e t i c u l a r pathway c a r r i e s i n f o r m a t i o n r e l a t e d t o the a v e r s i v e - m o t i v a t i o n a l a s p e c t s of p a i n whereas the s p i n o t h a l a m i c neurons r e l a y s e n s o r y - d i s c r i m i n i t i v e i n f o r m a t i o n (Melzak & Wal l , 1965). Recent e v i d e n c e s u g g e s t s t h a t a v a s t m a j o r i t y of the c e l l s o f the a n t e r o l a t e r a l f u n n i c u l i p r o j e c t t o the m i d b r a i n r a t h e r than the thalamus ( K e l l y , 1982). 16 F i g u r e 1. A f f e r e n t pathways i n v o l v e d i n n o c i c e p t i o n and e f f e r e n t pathways i n v o l v e d i n modu la t ion o f p a i n p e r c e p t i o n (ALF, a n t e r i o r l a t e r a l f u n i c u l u s ; DC, d o r s a l column; DCN, d o r s a l column n u c l e u s ; DLF, d o r s o l a t e r a l f u n i c u l u s ; ML, m e d i a l l e m n i s c u s ; NI, pr imary n o c i c e p t i v e s e n s o r y neurons; NRM, n u c l e u s raphe magnus; SR, s p i n o r e t i c u l a r pathway; ST, s p i n o t h a l a m i c pathway; T, tha lamus) . 18 D o r s a l column a f f e r e n t s . As l a r g e , f a s t c o n d u c t i n g sensory f i b e r s e n t e r the s p i n a l c o r d , a number ascend immedia te ly i n the d o r s a l column whi te matter . These axons synapse i n the d o r s a l column n u c l e i , which p r o j e c t s t o the m e d i a l l e m n i s c u s i n the b r a i n stem. I t i s g e n e r a l l y h e l d t h a t t h i s pathway p l a y s a modula tory r a t h e r than an i n f o r m a t i o n t r a n s d u c t i o n r o l e i n the p a i n system ( F i e l d s & Basbaum, 1978). E f f e r e n t M o d u l a t i o n A l though e f f e r e n t i n h i b i t i o n o f s p i n a l r e f l e x e s has been s t u d i e d s i n c e the t ime of S h e r r i n g t o n , o n l y r e c e n t l y has t h i s i n h i b i t i o n been r e l a t e d t o afferent s e n s o r y t r a n s m i s s i o n (c f F i e l d s & Basbaum, 1978). The d i s c o v e r y t h a t e l e c t r i c a l s t i m u l a t i o n o f v a r i o u s b r a i n s t e m l o c i p roduces i n h i b i t i o n of p a i n t r a n s m i s s i o n as w e l l as s p i n a l l y mediated r e f l e x e s n e c e s s i t a t e d the s tudy of efferent modu la t ion o f s e n s o r y t r a n s m i s s i o n . The o b s e r v a t i o n t h a t l o c a l m i c r o i n j e c t i o n o f morphine i n t o v a r i o u s b r a i n s t e m l o c i i n h i b i t e d r e s p o n d i n g to p a i n f u l s t i m u l i (Jacquet & L e j t h a , 1974; P e r t & Yaksh, 1974) l e d t o p o s t u l a t i o n o f an efferent i n h i b i t o r y mechanism f o r morphine a n a l g e s i a . S p e c i f i c a l l y , i n j e c t i o n o f morphine i n t o the p e r i a q u e d u c t a l gray (PAG) and s i t e s a d j a c e n t to the t h i r d v e n t r i c l e produces an i n h i b i t o r y e f f e c t on a s c e n d i n g n o c i c e p t i v e neurons (Herz, A lbus , Metys, S c h u b e r t & Teschemacher, 1970; J a c q u e t & L a j t h a , 1974; L o t t i , Lomax & George, 1965; Mayer & Murphin, 1976; P e r t & Yaksh, 1974; Sharpe, G a r n e t t e & C i c e r o , 1974; Yaksh, Yeung & Rudy, 1976). The PAG has been shown t o be h i g h i n o p i a t e b i n d i n g s i t e s 19 (Atweh & Kuhar, 1983; Kuhar, P e r t & Snyder, 1973). Some PAG c e l l s a r e immunoreact ive f o r endogenous o p i o i d p e p t i d e s ( C u e l l o , 1983). A l t h o u g h o p i a t e r e c e p t o r s have been l o c a l i z e d i n a r e a s o f the b r a i n , such as the amygdala and c o r p u s s t r i a t u m , o n l y o p i a t e i n j e c t i o n i n t o the P A G - p e r i v e n t r i c u l a r r e g i o n o f the m i d b r a i n p roduces a n a l g e s i a ( c f Mayer & P r i c e , 1976; Atweh & Kuhar, 1983). Among the p r o j e c t i o n s o f the PAG a r e t r a c t s from the d o r s a l and l a t e r a l PAG t o the n u c l e u s raphe magnus (NRM; C a r l t o n , L e i c h n e t z , Young & Mayer, 1983) and from the v e n t r a l PAG c a u d a l l y i n the d o r s o l a t e r a l f u n n i c u l u s (DLF) i n the s p i n a l c o r d (Watkins, G r i f f i n , L e i c h n e t z & Mayer, 1981). The NRM, i n t u r n , has major s e r o t o n e r g i c and n o n s e r o n t o n e r g i c e f f e r e n t s t o the DLF ( c f Mayer & P r i c e , 1976). Both the d i r e c t PAG and NRM e f f e r e n t s p r o j e c t t o r e g i o n s of the d o r s a l horn o f the s p i n a l c o r d t h a t a re known t o c o n t a i n p a i n s e n s i t i v e afferent neurons. L e s i o n s o f the DLF a b o l i s h the a n a l g e s i c e f f e c t o p i a t e m i c r o i n j e c t i o n (Mur f in , Bennet t & Mayer, 1976) and p e r i p h e r a l l y a d m i n i s t e r e d morphine ( P r i c e , Hayes, Bennet t , Wi lcox & Mayer, 1976). I t appears , then, t h a t the a n a l g e s i c e f f e c t o f o p i a t e s i s , a t l e a s t i n p a r t , mediated th rough an i n h i b i t o r y system o r i g i n a t i n g i n the PAG and decend ing e i t h e r th rough d i r e c t s p i n a l p r o j e c t i o n s or r e l a y e d v i a the NRM. SPA and O p i a t e A n a l g e s i a S e v e r a l r e v i e w s have ga thered c o n v i n c i n g p h y s i o l o g i c a l , p h a r m a c o l o g i c a l , and b e h a v i o r a l e v i d e n c e t o suggest a common n e u r a l s u b s t r a t e f o r SPA and o p i a t e a n a l g e s i a ( F i e l d s & Basbaum, 1978; Mayer & P r i c e , 1976; Watkins et. a l . , 1981). A s h o r t 20 summary o f t h a t ev idence f o l l o w s . P h y s i o l o g i c a l ev idence . Perhaps the most s t r i k i n g example o f a p h y s i o l o g i c a l commonal i ty i n the systems o f morphine a n a l g e s i a and SPA i s the p a r a l l e l i n t h e i r s i t e s o f a c t i o n . The s i t e s a t which a n a l g e s i a i s most r e a d i l y e l i c i t e d by morphine m i c r o i n j e c t i o n are a l o n g the PAG and p e r i v e n t r i c u l a r gray r e g i o n o f the bra instem. L i k e w i s e , SPA i s most r e a d i l y e l i c i t e d a t s i t e s e x t e n d i n g from the f o u r t h v e n t r i c l e a l o n g the aqueduct and around the t h i r d v e n t r i c l e (Snyder & Mat thysse , 1975, p. 95). In a d d i t i o n , both i n j e c t i o n o f morphine and s t i m u l a t i o n o f the PAG w i l l a l t e r the spontaneous a c t i v i t y o f neurons o f the NRM (Behbehani & F i e l d s , 1979; Behbehani & Pomeroy, 197B) and s p i n a l c o r d s e n s o r y i n t e r n e u r o n s r e p u t e d t o be i n v o l v e d i n p a i n t r a n s m i s s i o n ( F i e l d s & Anderson, 1978; L o v i c k , West & W o l s t e n c r o f t, 1978; O l i v e r a s , Benson, G u i l b a u d & L i e b e s k i n d , 1974; K i t a h t a , Koska, Taub, B o n i k o s & H o f f e r t , 1974). Fur thermore , l e s i o n s of the d o r s o l a t e r a l f u n n i c u l u s of the s p i n a l c o r d b l o c k both morphine a n a l g e s i a and SPA (Basbaum, C l a n t o n & F i e l d s , 1976). S t i m u l a t i o n o f the PAG i n human p a t i e n t s wi th c h r o n i c e l e c t r o d e s c a u s e s an i n c r e a s e i n o p i o i d p e p t i d e m e t a b o l i t e s i n the c e r e b r o s p i n a l f l u i d (Hosobuchi e t a l . , 1979). T h i s i n d i c a t e s the invo lvement o f an e n k e p h a l i n e r g i c synapse i n SPA. P h a r m a c o l o g i c a l Ev idence . A p r imary c r i t e r e o n f o r a t t r i b u t i n g an e f f e c t to o p i o i d m e d i a t i o n i s i t s r e v e r s a b i l i t y by the s p e c i f i c o p i a t e r e c e p t o r a n t a g o n i s t , na loxone. I t i s no s u p r i s e , then, t h a t the a n a l g e s i c e f f e c t o f i n t r a c r a n i a l 21 m i c r i n j e c t i o n o f o p i a t e s i n t o the PAC i s a n t a g o n i z e d by p e r i p h e r a l na loxone (Ma l ick & G o l d s t e i n , 1977). The f i n d i n g t h a t SPA i s a t l e a s t p a r t i a l l y n a l o x o n e - r e v e r s a b l e l e n d s s t r o n g s u p p o r t t o M a y e r ' s c o n c l u s i o n ( A k i l , Mayer & L i e b e s k i n d , 1976). As p r e v i o u s l y s t a t e d , morphine a n a l g e s i a i s thought to be mediated by a s p i n a l s e r o t o n e r g i c synapse. D e p l e t i o n o f s e r o t o n i n by pCPA has a d e l e t e r i o u s e f f e c t on morphine a n a l g e s i a (Sugrue, 1979; Tenen, 1968; Vogt, 1974) as w e l l as SPA ( A k i l & Mayer, 1972; A k i l & L i e b e s k i n d , 1975). R e c e n t l y , o t h e r s have found c o n t r a d i c t o r y da ta , w i th d e p l e t i o n of s p i n a l s e r o t o n i n h a v i n g l i t t l e e f f e c t on SPA (Johannesson, Watkins, C a r l t o n & Mayer, 1982). The a u t h o r s s u g g e s t p a r a l l e l d e s c e n d i n g i n h i b i t o r y systems, one s e r o t o n e r g i c and the o t h e r n o r a d r e n e r g i c . B e h a v i o r a l Ev idence . Morphine and PAG s t i m u l a t i o n produce a s t r o n g s u p p r e s s i o n o f c e r t a i n s p i n a l r e f l e x e s , such as the t a i l - f l i c k r e s p o n s e , which a r e r e l a t i v e l y u n a f f e c t e d by n o n - n a r c o t i c drugs (Grumbach, 1966; Mayer & L i e b e s k i n d , 1974). When a d m i n i s t e r e d i n d a i l y 1 min s e s s i o n s t o l e r a n c e d e v e l o p s t o the a n a l g e s i c e f f e c t o f the s t i m u l a t i o n a t a p p r o x i m a t e l y the same r a t e as t o l e r a n c e t o morphine (Mayer & Hayes, 1975). Repeated i n j e c t i o n of morphine a t t e n u a t e s the a n a l g e s i c e f f e c t o f PAG s t i m u l a t i o n (Mayer & Hayes, 1975). In o t h e r words, morphine and SPA are a t l e a s t p a r t i a l l y c r o s s - t o l e r a n t . 22 R a t i o n a l e To summarize/ 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 o f o p i a t e d rugs seems t o be c o n t r o l l e d by P a v l o v i a n a s s o c i a t i o n s between the c u e s p r e d i c t i v e o f drug a d m i n i s t r a t i o n and the drug e x p e r i e n c e . I t has been proposed t h a t a homeosta t i c compensatory response / a n t a g o n i s t i c t o the drug e f f e c t i s c o n d i t i o n e d to those e n v i r o n m e n t a l cues t h a t a r e p r e d i c t i v e o f the i n j e c t i o n ( S i e g e l / 1975). The a n a l g e s i c a c t i o n o f both morphine and e l e c t r i c a l s t i m u l a t i o n o f the PAG appears t o be mediated through descend ing i n h i b i t i o n o f s p i n a l n o c i c e p t i v e a f f e r e n t s . T h e r e f o r e / t h e r e i s c o n s i d e r a b l e e v i d e n c e t h a t s u g g e s t s a common n e u r a l s u b s t r a t e f o r SPA and morphine a n a l g e s i a . G iven t h i s apparent s i m i l a r i t y between the a n a l g e s i c mechanisms o f o p i a t e drugs and SPA* t o l e r a n c e to SPA s h o u l d a l s o be c o n t r o l l e d by P a v l o v i a n a s s o c i a t i o n s . The a n a l g e s i a t h a t i s produced by PAG s t i m u l a t i o n i s r e l a t i v e l y f r e e o f the m u l t i p l e " s i d e e f f e c t s " t h a t n a r c o t i c a n a l g e s i c s are known t o produce (Mayer & P r i c e / 1976). A d e m o n s t r a t i o n o f c o n d i t i o n e d t o l e r a n c e t o SPA w i l l p r o v i d e a paradigm t h a t i s p a r t i c u l a r l y p r o m i s i n g i n the e x a m i n a t i o n o f the p h y s i o l o g i c a l mechanisms o f these p r o c e s s e s . S i n c e no drug i s a d m i n i s t e r e d / unconfounded b i o c h e m i c a l a n a l y s i s o f CNS r e g i o n s may p r o v i d e c l u e s t o the i d e n t i t y o f t r a n s m i t t e r s t h a t may be i n v o l v e d i n c o n d i t i o n e d t o l e r a n c e . P h y s i o l o g i c a l m a n i p u l a t i o n s of b r a i n r e g i o n s p u t a t i v e l y i n v o l v e d i n l e a r n i n g the c o n d i t i o n a l homeosta t ic response may be made w i thout p o s s i b l e i n t e r a c t i o n w i th l o c a l 23 o p i o i d r e c e p t o r s . F i n a l l y / compar ison t o o t h e r l o c i o f s t i m u l a t i o n p romises a d d i t i o n a l i n s i g h t i n t o a n a t o m i c a l and p h y s i o l o g i c a l a s p e c t s o f the n o c i c e p t i v e system. In the morphine a n a l g e s i a paradigm, c o n d i t i o n e d t o l e r a n c e has been demonstra ted w i th s e v e r a l measures o f n o c i c e p t i o n . S i e g e l (1975, 1976, 1977, 1978, 1981) has used the hot p l a t e method and a paw p r e s s u r e an a lg e s io me t e r . T i f f a n y and h i s c o - w o r k e r s ( T i f f a n y & Baker, 1981; T i f f a n y et. a l . , 1983) have used the f l i n c h / j u m p e l e c t r i c shock t e s t , and Advokat (1980) has used the t a i l - f l i c k method o f D'Amour and Smith (1941). The f o r m a l i n w r i t h i n g t e s t has proved t o be r e l a t i v e l y u n a f f e c t e d by e n v i r o n m e n t a l m a n i p u l a t i o n s (Abbott , Melzack & Leber , 1982). Of t h e s e t e s t s , o n l y the t a i l - f l i c k measure used by Advokat i s a s p i n a l l y mediated n o c i c e p t i v e response . The remainder r e q u i r e c o o r d i n a t e d movement t o escape the p a i n f u l s t i m u l u s . The advantage o f u s i n g a response t h a t i s mediated a t the l e v e l o f the s p i n a l c o r d i s t h r e e f o l d . F i r s t , s p i n a l r e f l e x e s a r e r e l a t i v e l y u n a f f e c t e d by n o n - o p i a t e a n a l g e s i c s . Use o f a s p i n a l r e f l e x then, l e n d s s u p p o r t t o the c o n t e n t i o n t h a t the b r a i n - s t i m u l a t i o n i s a f f e c t i n g a decend ing i n h i b i t o r y o p i o i d system. Second, the use o f a s p i n a l r e f l e x e l i m i n a t e s the p o s s i b i l i t y o f o p e r a n t l y c o n d i t i o n e d b e h a v i o r a l t o l e r a n c e as d e s c r i b e d by Dews (1962). F i n a l l y , s i n c e a s p i n a l r e f l e x e l i m i n a t e s c o o r d i n a t e d motor r e s p o n s e s , i t may be p a r t i c u l a r l y u s e f u l f o r f u t u r e examina t ion o f 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 c o n d i t i o n e d t o l e r a n c e (Advokat, 1980). The f o c u s e d l i g h t beam t a i l - f l i c k of D'Amour and Smith, has 24 a d i s t i n c t . d i s a d v a n t a g e , however. An imals are r i g i d l y r e s t r a i n e d , and t h i s may affect n o c i c e p t i o n . A m o d i f i c a t i o n o f t h i s method, deve loped by Cray and Umedely (In P r e p a r a t i o n ) and used r e c e n t l y by Abbot t , et . a l . (1982) w i l l be used i n the p r e s e n t exper iments . T h i s method uses r e l a t i v e l y u n r e s t r a i n e d an ima ls t o a v o i d s t r e s s e f f e c t s . Fur thermore , an automat ic t i m i n g c i r c u i t r e d u c e s the chance o f exper imentor b i a s . The f o l l o w i n g exper iments p r o v i d e c o n c l u s i v e ev idence t h a t SPA t o l e r a n c e can be e x t i n g u i s h e d , i s s i t u a t i o n s p e c i f i c , and can be accounted f o r by a c o n d i t i o n a l h o m e o s t a t i c compensatory mechanism. 25 EXPERIMENT 1: EXTINCTION OF TOLERANCE TO STIMULATION PRODUCED ANALGESIA When a CS i s f o l l o w e d by a UCS, o r an i n s t r u m e n t a l r e s p o n s e by a r e i n f o r c i n g event , the p r o b a b i l i t y o f the CR o r an i n s t r u m e n t a l response u s u a l l y i n c r e a s e s . I f a l l e l s e i s h e l d c o n s t a n t , the o m i s s i o n o f the UCS or rexnfarcer d e f i n e s the o p e r a t i o n o f e x p e r i m e n t a l e x t i n c t i o n and u s u a l l y r e s u l t s i n a d e c r e a s e i n the p r o b a b i l i t y o f r e s p o n d i n g (Mackintosh, 1974, p. 405). A un ique p r e d i c t i o n o f the c o n d i t i o n i n g model o f t o l e r a n c e i s t h a t p r e s e n t a t i o n o f an e n v i r o n m e n t a l CS not f a l l o w e d by the p h a r m a c o l o g i c a l agent s h o u l d a t t e n u a t e an e s t a b l i s h e d t o l e r a n c e . In o t h e r words, t o l e r a n c e s h o u l d be s u b j e c t t o the decrementa l e f f e c t o f e x t i n c t i o n . In c o n t r a s t t o t h i s p r e d i c t i o n o f C o n d i t i o n i n g Theory, p h y s i o l o g i c a l t h e o r i e s o f t o l e r a n c e would p r e d i c t tha t , i f e x p e r i m e n t a l and c o n t r o l groups r e c e i v e a drug on e x a c t l y the same s c h e d u l e , they s h o u l d deve lop t o l e r a n c e t o the same degree, r e g a r d l e s s o f exposure to the cues. In the morphine a n a l g e s i a paradigm, r e p e a t e d p a i r i n g s o f e n v i r o n m e n t a l cues w i t h a morphine i n j e c t i o n produces t o l e r a n c e t o the d r u g ' s a n a l g e s i c e f f e c t . S e v e r a l p r e s e n t a t i o n s o f the c o n d i t i o n a l e n v i r o n m e n t a l cues p a i r e d w i th a p l a c e b o i n j e c t i o n w i l l a t t e n u a t e t h i s t o l e r a n c e . Fur thermore , s u b j e c t s t h a t a re not exposed t o the e n v i r o n m e n t a l CS d u r i n g t h i s e x t i n c t i o n phase remain 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 o f morphine ( S i e g e l , 1975, 1977, 1978). C l e a r l y , n o n a s s o c i a t i v e models cannot account f o r the e x t i n c t i o n o f morphine t o l e r a n c e by p r e s e n t a t i o n o f e n v i r o n m e n t a l cues. 26 As p r e v i o u s l y noted , the a n a l g e s i c e f f e c t o f PAG s t i m u l a t i o n d e v e l o p s t o l e r a n c e w i t h r e p e a t e d t r i a l s . Apparent commona l i t i es between morphine a n a l g e s i a and SPA s u g g e s t tha t . l i k e morphine, t o l e r a n c e t o SPA s h o u l d be a t t e n u a t e d by p r e s e n t a t i o n o f c o n d i t i o n a l e n v i r o n m e n t a l cues, but not by the t ime d e l a y a lone. Exper iment 1 t e s t s t h i s h y p o t h e s i s . Method S u b j e c t s . T w e n t y - f o u r male. Long-Evans . hooded r a t s (Canadian B r e e d i n g Farms L a b o r a t o r i e s . S t Constant . Quebec) were housed i n d i v i d u a l l y w i th ad l i b a c c e s s t o l a b chow (Pur ina ) and water (B. C. Hydro) . A l i g h t / d a r k c y c l e o f 12/12 hrs . a p p r o x i m a t i n g normal day—night hours , was ma in ta ined throughout the experiment. At the t ime of s u r g e r y . an ima ls weighed 300-400g. Surgery . Each a n i m a l was a n e s t h e t i z e d w i th sodium p e n t o b a r b i t o l (Somni to l . M. T. C. P h a r m a c e u t i c a l s . Hami l ton. O n t a r i o . Canada. 65 mg/kg). U s i n g a s t a n d a r d s t e r e o t a x i c i n s t r u m e n t w i th the i n c i s o r bar 5. 0 mm above the i n t e r a u r a l l i n e , a b i p o l a r e l e c t r o d e (0. 250 mm. P l a s t i c P r o d u c t s . Roanoke. V i r g i n i a ) was aimed a t the PAG, lowered, and f i x e d t o the s k u l l w i th j e w l e r ' s screws and a c r y l i c cement. The c o o r d i n a t e s were as f o l l o w s : 0. 6 mm a n t e r i o r t o the i n t e r a u r a l l i n e . 0. 7mm l a t e r a l to the s a g g i t a l s u t u r e , and 6. 0 mm v e n t r a l t o the d o r s a l s k u l l s u r f a c e . At l e a s t 10 days were a l l o w e d f o r r e c o v e r y from surgery . 27 H i s t o l o g y . A l l s u b j e c t s were s a c r i f i c e d by carbon d i o x i d e a s p h i x i a t i o n and immedia te ly p e r f u s e d t r a n s c a r d i a l l y w i th 0. 9% NaCl f o l l o w e d by 107. b u f f e r e d n e u t r a l f o r m a l i n (Luna, 1968, p3). The b r a i n s were removed and f i x e d i n the f o r m a l i n s o l u t i o n f o r a t l e a s t 24 hr. , frozen and s e c t i o n e d a t 30 microns and s t a i n e d a c c o r d i n g t o a m o d i f i e d K l u v e r - B a r r e r a method (Luna, 1968, pp 203-204) f o r m y e l i n and nerve c e l l s . E l e c t r o d e p lacements were c o n f i r m e d by two independent o b s e r v e r s . Apparatus . 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 was d e l i v e r e d through 80 cm l e a d s ( P l a s t i c P r o d u c t s ) , a t t a c h e d t o commutators and suspended from above t o a v o i d t a n g l i n g . Two c o n s t a n t c u r r e n t s t i m u l a t o r s were programmed t o d e l i v e r 60 hz Ac t o the e l e c t r o d e s i n t r a i n s of 200 msec wi th a 300 msec i n t e r - s t i m u l a t i o n i n t e r v a l . S t i m u l a t i o n s e s s i o n s were c a r r i e d out i n two p l e x i g l a s chambers (21. 5 x 30. 5 x 45. 5 cm h i g h ) . Each chamber was p l a c e d i n a s e p a r a t e i n s u l a t e d e n c l o s u r e , v e n t i l a t e d by a s m a l l fan. F o r a n a l g e s i a t e s t i n g , each a n i m a l was p l a c e d i n t o a s m a l l t u b u l a r chamber (7. 5 cm d i a x 21. 5 cm l e n g t h ) w i th an a p e r t u r e i n the r e a r th rough which h i s t a i l was drawn. A p p r o x i m a t e l y 3 i n o f the t a i l was submersed i n a 52 C water bath and the l a t e n c y t o remove the t a i l was recorded . Procedure . B a s e l i n e t a i l - f l i c k l a t e n c i e s were r e c o r d e d over 4 d a i l y s e s s i o n s ; the f i r s t 3 measurements were taken i n the c o l o n y room and the f o u r t h i n a s e p a r a t e t e s t i n g room. On the l a s t b a s e l i n e day, a f t e r a n a l g e s i a t e s t i n g , b r a i n s t i m u l a t i o n c u r r e n t i n t e n s i t y was determined f o r each s u b j e c t i n a s e s s i o n 28 l a s t i n g l e s s than 1 min. The c u r r e n t was i n i t i a l l y s e t a t 10 ua< and incremented i n 2 ua s teps . When a motor a r t i f a c t was d i s p l a y e d the c u r r e n t i n t e n s i t y was reduced by 2 ua and t h i s i n t e n s i t y was used th roughout the experiment. A c e i l i n g o f 50 ua uas main ta ined . On each s t i m u l a t i o n s e s s i o n , an ima ls were t r a n s p o r t e d t o the t e s t i n g room and p l a c e d i n t o one o f f i v e chambers i n a h o l d i n g box f o r 15 min. S a n i c e l , s c e n t e d wi th 10 ml o f 10"/. ( v o l / v o l H20) almond e x t r a c t s o l u t i o n (Brooke Bond I n c . , B e l l e v i l l e , O n t a r i o ) , c o v e r e d the bottom o f the chambers. The t e s t i n g room was i l l u m i n a t e d w i th a dim r e d l i g h t and the v e n t i l a t i o n f a n s p r o v i d e d a d i s t i n c t i v e background n o i s e . A f t e r 15 min the an ima ls were removed from the h o l d i n g chamber, c o n n e c t e d t o the b r a i n s t i m u l a t o r , and p l a c e d i n the p l e x i g l a s s t i m u l a t i o n chamber. T r a i n s o f e l e c t r i c a l s t i m u l a t i o n were then d e l i v e r e d f o r a 5 min p e r i o d . The a n a l g e s i c e f f e c t o f the b r a i n s t i m u l a t i o n was determined immedia te ly by measur ing t a i l - f l i c k l a t e n c y as d e s c r i b e d above. An ima ls w i th t a i l - f l i c k l a t e n c i e s o f a t l e a s t 1507. o f b a s e l i n e s c o r e s were c o n s i d e r e d t o be a n a l g e s i c and were c o n t i n u e d i n t o the t o l e r a n c e phase o f the exper iment . S i x t e e n o f the t w e n t y - f o u r s u b j e c t s met t h i s c r i t e r e o n . T a i l - f l i c k l a t e n c i e s were measured d a i l y a f t e r s i x a d d i t i o n a l s t i m u l a t i o n s e s s i o n s . An imals were then randomly a s s i g n e d t o two groups: EXTINCTION and CONTROL. For the next 12 s e s s i o n s , an ima ls i n the EXTINCTION group (n=8) r e c e i v e d a s i m i l a r t rea tment t o t h a t used i n the t o l e r a n c e phase, w i th the e x c e p t i o n o f d i s c o n n e c t i n g the 29 b r a i n s t i m u l a t o r •From the l e a d s a t t a c h e d to the c h r o n i c e l e c t r o d e assembly and l e a v i n g the water ba th a t room temperature (21 C). T h i s p r o c e d u r e a l l o w e d r e p e a t e d p r e s e n t a t i o n o f the cues t h a t had p r e d i c t e d SPA ( i . e. e x t i n c t i o n t r i a l s ) . S u b j e c t s i n the CONTROL group (n=8) were l e f t i n t h e i r home cages throughout t h i s 12 day p e r i o d . The e x t i n c t i o n phase was f o l l o w e d by 4 d a i l y t e s t s e s s i o n s i n which b r a i n s t i m u l a t i o n was a g a i n d e l i v e r e d p r i o r t o measurement o f t a i l - f l i c k l a t e n c i e s i n heated water (52 C). R e s u l t s H i s t o l o g y . A l l e l e c t r o d e p lacements were i n , o r b o r d e r i n g on, the PAG, 0-2 mm r o s t r a l t o the t h i r d v e n t r i c l e (F ig . 2). S t i m u l a t i o n Produced A n a l g e s i a . U n l e s s o t h e r w i s e noted, compar isons a r e by a mixed d e s i g n a n a l y s i s o f variance per formed by computer u s i n g the S t a t i s t i c a l Package f o r the S o c i a l S c i e n c e s , v e r s i o n 9. E l e c t r i c a l s t i m u l a t i o n o f the PAG i n c r e a s e d t a i l - f l i c k l a t e n c i e s from mean b a s e l i n e s c o r e s o f 3. 05 sec and 2. 86 sec t o 7. 49 sec and 7. 29 sec f o r the EXTINCTION group and CONTROL group r e s p e c t i v e l y (F ig . 3). The compar ison f o r s e s s i o n s 1 and 2 showed a s i g n i f i c a n t main e f f e c t f o r s e s s i o n s CF(1, 14) = 98. 06, p < . 001]. T o l e r a n c e deve loped e q u a l l y f o r the two groups over the seven s t i m u l a t i o n s e s s i o n s ( s e s s i o n s 2-8) , wi th mean t a i l - f l i c k l a t e n c i e s d r o p p i n g t o 3. 74 sec f o r the EXTINCTION group and 3. 58 sec f o r CONTROL group an imals . The compar ison showed a s i g n i f i c a n t s e s s i o n s e f f e c t CF(6, 14)= = 28. 80, p < . 0013. 30 F i g u r e 2. E l e c t r o d e p lacements of r a t s i n the EXTINCTION group and CONTROL group from Exper iment 1. B r a i n s e c t i o n s mere taken from P e l l e g r i n o . P e l l e g r i n o » and Cushman (1979). 32 F i g u r e 3. Mean t a i l - f l i c k l a t e n c i e s i n seconds f o r the EXTINCTION and CONTROL groups i n Exper iment 1. S e s s i o n 1 r e p r e s e n t s the f i n a l ( f o u r t h ) b a s e l i n e s e s s i o n . On s e s s i o n s 2-8 a l l r a t s r e c e i v e d p a i r i n g s o f the e n v i r o n m e n t a l cues and b r a i n - s t i m u l a t i o n . On s e s s i o n s 9-20 r a t s i n the EXTINCTION group were exposed t o the e n v i r o n m e n t a l cues but were not s t i m u l a t e d . Rats i n the CONTROL group were l e f t u n d i s t u r b e d i n t h e i r cages d u r i n g t h i s 12-day p e r i o d . On t e s t s e s s i o n s ( s e s s i o n s 21-24) exposure t o e n v i r o n m e n t a l cues a g a i n p receded b r a i n s t i m u l a t i o n f o r a l l r a t s . 31 O 10 LU > o z LU _J o z < LU 8 - • — EXTINCTION - O - CONTROL i Y J I I I L 1 2 3 4 5 6 7 8 Y/- J i i 21 22 23 24 SESSION 34 A f t e r 12 e x t i n c t i o n t r i a l s ( s e s s i o n s 9-20) e l e c t r i c a l s t i m u l a t i o n o f the PAG a g a i n produced an a n a l g e s i c e f f e c t , i n c r e a s i n g the mean t a i l - f l i c k l a t e n c y o f t h i s group t o 5. 68 sec . The CONTROL group remained t o l e r a n t t o the SPA d e s p i t e 12 days i n t h e i r home cages, and had a mean t a i l - f l i c k l a t e n c y o f 3. 35 sec a f t e r s t i m u l a t i o n i n s e s s i o n 21. Group d i f f e r e n c e s were r e f l e c t e d i n a s i g n i f i c a n t s e s s i o n (8 and 21) by t rea tment i n t e r a c t i o n CF<1, 14) = 14.52. p < . 0 0 1 1 T a i l - f l i c k l a t e n c i e s o f the EXTINCTION and CONTROL groups mere s i g n i f i c a n t l y d i f f e r e n t on the f i r s t t e s t s e s s i o n ( s e s s i o n 21. t = 4. 20. p < . 001). T o l e r a n c e t o SPA was r e a q u i r e d i n the EXTINCTION group a f t e r f o u r s t i m u l a t i o n s e s s i o n s , as t a i l - f l i c k l a t e n c i e s r e t u r n e d t o 3. 82 sec . T h i s i s r e f l e c t e d i n a s i g n i f i c a n t s e s s i o n s by t rea tment i n t e r a c t i o n f o r s e s s i o n s 21-24 CF(3, 14) = 3. 6. p = .053. A Duncan 's M u l t i p l e Range t e s t CCd(56) = . 317k3 c o n f i r m e d s i g n i f i c a n t d i f f e r e n c e s f o r compar isons o f s e s s i o n s 21 and 23 (p < . 0 5 ) , but not f o r s e s s i o n s 22 and 24. D i s c u s s i o n The r e s u l t s o f Exper iment 1 show t h a t t o l e r a n c e to the a n a l g e s i c e f f e c t o f SPA can be a t t e n u a t e d by an e x t i n c t i o n procedure . Repeated s t i m u l a t i o n of the PAG i n d u c e d t o l e r a n c e t o the s t i m u l a t i o n , r e p l i c a t i n g the r e s u l t s o f Mayer and Hayes (1975). S u b j e c t s p r e s e n t e d w i th the e n v i r o n m e n t a l cues which had p r e d i c t e d s t i m u l a t i o n f o r twe lve s e s s i o n s (EXTINCTION group) showed an a t t e n u a t e d t o l e r a n c e l e v e l . That i s , t h e i r t a i l - f l i c k l a t e n c i e s were l o n g e r than on the l a s t day o f the t o l e r a n c e phase. S u b j e c t s r e m a i n i n g i n t h e i r home cages f o r the same 35 twelve day p e r i o d (CONTROL group) p r o v i d e d a c o n t r o l f o r any t ime-dependent a t t e n u a t i o n o f t o l e r a n c e . These a n i m a l s remained t o l e r a n t t o the PAG s t i m u l a t i o n / w i th t a i l - f l i c k l a t e n c i e s r e m a i n i n g a t p r e - d e l a y l e v e l s . I t i s impor tan t t o emphasize t h a t the EXTINCTION and CONTROL groups r e c e i v e d s t i m u l a t i o n on e x a c t l y the same s c h e d u l e throughout t h i s exper iment . The o n l y d i f f e r e n c e between the groups was exposure t o the e n v i r o n m e n t a l cues d u r i n g the twelve e x t i n c t i o n s e s s i o n s . Only t h e o r i e s s t r e s s i n g a r o l e f o r an a s s o c i a t i v e mechanism i n t o l e r a n c e c o u l d p o s s i b l y p r e d i c t t h a t t h e s e e x t i n c t i o n t r i a l s c o u l d a t t e n u a t e t o l e r a n c e t o SPA. A l though the e f f e c t o f the e x t i n c t i o n t r i a l s i s r o b u s t (p < . 001) i the a n a l g e s i c e f f e c t o f s t i m u l a t i o n has not been r e - e s t a b l i s h e d t o p r e - t o l e r a n c e l e v e l s . S e v e r a l e x p l a n a t i o n s a re p o s s i b l e . F i r s t / i t i s easy t o i n f e r p h y s i o l o g i c a l mechanisms t o account f o r a t l e a s t p a r t o f the t o l e r a n c e t h a t d e v e l o p s to SPA. Such a p h y s i o l o g i c a l mechanism would summate w i th c o n d i t i o n e d t o l e r a n c e / and be r e l a t i v e l y u n a f f e c t e d by e n v i r o n m e n t a l m a n i p u l a t i o n s . A second p o s s i b i l i t y i s t h a t the number o f e x t i n c t i o n t r i a l s was i n s u f f i c i e n t t o c o m p l e t e l y a t t e n u a t e t o l e r a n c e . A t h i r d p o s s i b i l i t y i n v o k e s the concept o f g e n e r a l i z a t i o n decrement. G e n e r a l i z a t i o n decrement r e f e r s t o the d e c r e a s e i n the a b i l i t y o f a s t i m u l u s t o e l i c i t a CR as the d i s c r e p e n c y between the s t i m u l u s and the CS i n c r e a s e s . B r a i n - s t i m u l a t i o n i s known to have cue p r o p e r t i e s o f i t s own ( P h i l l i p s & LePiane , 1978; P h i l l i p s & MacDonald, 1979; S t u t z & M a r o l i , 1978). The absence of the s t i m u l a t i o n may have a l t e r e d 36 the CS d u r i n g e x t i n c t i o n t r i a l s , p r e v e n t i n g complete e x t i n c t i o n . When the f u l l CS (env i ronmenta l cues + s t i m u l a t i o n ) i s r e i n t r o d u c e d on t e s t s e s s i o n s , an a t t e n u a t e d CR may be e l i c i t e d d u r i n g the f i v e min s t i m u l a t i o n s e s s i o n . I t i s i m p o s s i b l e t o d i s t i n g u i s h between t h e s e e x p l a n a t i o n s on the b a s i s of the p r e s e n t data. 37 EXPERIMENT 2: CONTEXT SPECIFICITY OF TOLERANCE TO STIMULATION PRODUCED ANALGESIA The term " c o n t e x t s p e c i f i c i t y " i m p l i e s t h a t a CS-UCS a s s o c i a t i o n i s dependent upon the envi ronment i n which i t i s formed. A CS t h a t e l i c i t s a CR i n one environment may not e l i c i t t h a t CR when p r e s e n t e d i n another envi ronment (eg. Dweck & Wagner, 19701 M a r l i n , 1982). Presumably, a s s o c i a t i o n s between a CS and f e a t u r e s o f the envi ronment a re formed d u r i n g c o n d i t i o n i n g , making the envi ronment p a r t o f the CS. When the CS i s p r e s e n t e d i n an environment t h a t i s s i g n i f i c a n t l y d i f f e r e n t than the t r a i n i n g envi ronment the CS has been changed and a g e n e r a l i z a t i o n decrement o c c u r s ( R e s c o r l a & Wagner, 1972). S i e g e l (1975, 1976) has demonstra ted t h a t t o l e r a n c e t o m o r p h i n e ' s a n a l g e s i c e f f e c t , as t e s t e d w i th the h o t p l a t e method and paw p i n c h a n a l g e s i o m e t e r and deve loped i n one environment , i s a t t e n u a t e d when the drug i s g i v e n i n an a l t e r n a t e environment. Of c o u r s e , an ima ls t e s t e d i n the same environment r e t a i n e d t o l e r a n c e . T h i s e f f e c t has been r e p l i c a t e d u s i n g the r a d i a n t heat t a i l - f l i c k measure (Advokat, 1980) and f l i n c h / j u m p shock t e s t ( T i f f a n y & Baker, 1981). S i n c e the a n a l g e s i c e f f e c t s o f morphine and PAG s t i m u l a t i o n may o p e r a t e by a common mechanism, t o l e r a n c e t o SPA, l i k e t o l e r a n c e t o morphine a n a l g e s i a , s h o u l d be dependent upon the c o n t e x t i n which i t i s developed. A c c o r d i n g t o a P a v l o v i a n model, s u b j e c t s t h a t d e v e l o p t o l e r a n c e to SPA i n one environment s h o u l d respond i n a r e l a t i v e l y n o n t o l e r a n t manner when t e s t e d i n 38 an d i f f e r e n t environment , p r o v i d e d t h a t the two env i ronments a r e s u f f i c i e n t l y d i s t i n c t . S u b j e c t s t h a t deve lop t o l e r a n c e and are t e s t e d i n the same environment s h o u l d remain t o l e r a n t t o the b r a i n - s t i m u l a t i o n . I f the s c h e d u l e o f s t i m u l a t i o n i s i d e n t i c a l f o r the two groups, p h y s i o l o g i c a l t h e o r i e s would p r e d i c t e q u i v a l e n t t o l e r a n c e on t e s t s e s s i o n s , i r r e s p e c t i v e o f the contex t . Exper iment 2 was d e s i g n e d t o t e s t t h e s e hypotheses . Method S u b j e c t s . T h i r t y male, Long-Evans r a t s were p r e p a r e d a c c o r d i n g t o the methods d e s c r i b e d i n Exper iment 1. At the end o f the exper iment an ima ls were a g a i n s a c r i f i c e d and b r a i n s removed f o r h i s t o l o g i c a l examinat ion . Apparatus . The two envi ronments used i n t h i s exper iment were the t e s t i n g room used i n Exper iment 1 and the a n i m a l s ' c o l o n y room. By u s i n g the environment i n which the a n i m a l s l i v e as the f i n a l t e s t i n g environment , n o v e l t y was e l i m i n a t e d as a p o s s i b l e cause o f a n a l g e s i a on t e s t s e s s i o n s . S t i m u l a t i o n t r a i n s were d e l i v e r e d by a s i n g l e c o n s t a n t c u r r e n t s t i m u l a t o r , programmed as i n Exper iment 1. The s t i m u l a t o r was c a r r i e d between the two env i ronments t o c l o s e l y match s t i m u l a t i o n parameters . Appara tus i n the s e p a r a t e t e s t i n g room was i d e n t i c a l t o t h a t i n Exper iment 1. Appara tus i n the c o l o n y room was i d e n t i c a l , except t h a t the s t i m u l a t i o n chamber was not l o c a t e d i n a s o u n d - a t t e n u a t i n g e n c l o s u r e . Procedure . As i n Exper iment 1, b a s e l i n e t a i l - f l i c k measurements were r e c o r d e d over f o u r d a i l y s e s s i o n s w i th the 39 f i r s t t h r e e measurements taken i n the c o l o n y room and the f o u r t h measurement i n the s e p a r a t e t e s t i n g environment. S t i m u l a t i o n i n t e n s i t i e s mere determined a c c o r d i n g t o the method used i n Exper iment 1. An ima ls were then randomly a s s i g n e d t o two groups: ENVIRONMENT SAME and ENVIRONMENT DIFFERENT. Mean s t i m u l a t i o n f o r the ENVIRONMENT SAME group was 17. 7 ua, w i th a minimum o f 10 ua and a maximum o f 45 ua. F o r the ENVIRONMENT DIFFERENT group, mean s t i m u l a t i o n i n t e n s i t y was 20. 1 ua, w i th a minimum o f 10 ua and a maximum o f 41 ua. On each s t i m u l a t i o n day, each an ima l i n the ENVIRONMENT SAME group was taken from h i s cage and immedia te ly a t t a c h e d t o the s t i m u l a t i o n appara tus . F i v e min o f s t i m u l a t i o n t r a i n s preceded a t a i l - f l i c k a n a l g e s i a t e s t . S u b j e c t s were immedia te ly r e t u r n e d t o t h e i r cages. The c o l o n y room was w e l l l i g h t e d and a c c e s s was r e s t r i c t e d t o m a i n t a i n qu ie t . An imals i n the ENVIRONMENT DIFFERENT group were t r e a t e d as i n Exper iment 1. S p e c i f i c a l l y , they were e n c l o s e d i n the a lmond-scented h o l d i n g chamber f o r f i f t e e n minutes p r e c e d i n g the f i v e minutes o f s t i m u l a t i o n and a t a i l - f l i c k t e s t . Only a dim r e d l i g h t i l l u m i n a t e d the room, and v e n t i l a t i o n f a n s p r o v i d e d background n o i s e . S u b j e c t s meet ing the 150/. o f b a s e l i n e a n a l g e s i a c r i t e r i a r e c e i v e d an a d d i t i o n a l s i x s e s s i o n s o f s t i m u l a t i o n i n t h e i r r e s p e c t i v e envi ronments . Nine an ima ls i n each group met t h i s c r i t e r e a and were c o n t i n u e d i n t o the t o l e r a n c e phase. „ The s e v e n - s e s s i o n t o l e r a n c e phase was f o l l o w e d by f o u r days 40 o f • tes t ing , i n which a i l s u b j e c t s r e c e i v e d s t i m u l a t i o n i n the c o l o n y environment. C o n d i t i o n s were i d e n t i c a l to those o f the ENVIRONMENT SAME group d u r i n g the t o l e r a n c e phase. T h i s p r o c e d u r e e l i m i n a t e d the cues t h a t had p r e d i c t e d SPA f o r the ENVIRONMENT DIFFERENT group w h i l e m a i n t a i n i n g the cues f o r the ENVIRONMENT SAME group. R e s u l t s Histo logu, , A l l but t h r e e e l e c t r o d e p lacements e l i c i t i n g a n a l g e s i a were i n , o r b o r d e r i n g on the PAG. The h i s t o l o g y of one s u b j e c t was l o s t . A l l p lacements not e l i c i t i n g a n a l g e s i a were i n the PAG (F ig . 4). S t i m u l a t i o n Produced A n a l g e s i a . Mixed d e s i g n ANOVAs were a g a i n used f o r s t a t i s t i c a l compar isons. except where noted. Lack o f d i f f e r e n c e s between b a s e l i n e s e s s i o n s 3 and 4 ( s e s s i o n s 1 and 2, F i g . 5) were c o n f i r m e d by a n o n s i g n i f i c a n t main e f f e c t f o r s e s s i o n s CF(1, 16)=0. 247, p>0. 5 1 The f i n a l b a s e l i n e s e s s i o n was used f o r the remainder o f the s t a t i s t i c a l compar isons. S t i m u l a t i o n of the PAG i n c r e a s e d mean t a i l - f l i c k l a t e n c i e s from 3. 79 and 3. 98 t o 6. 89 and 7. 76 i n the ENVIRONMENT DIFFERENT and ENVIRONMENT SAME group, r e s p e c t i v e l y . A s i g n i f i c a n t s e s s i o n s e f f e c t f o r the compar ison o f s e s s i o n s 2 and 3 CF(1, 16) = 107. 186, p < 0. 0013 c o n f i r m e d t h i s a n a l g e s i c e f f e c t . With repea ted s t i m u l a t i o n i n s e s s i o n s 3 th rough 9, t o l e r a n c e deve loped e q u a l l y f o r the two groups. Mean t a i l - f l i c k l a t e n c i e s dropped t o 3. 77 f o r the ENVIRONMENT DIFFERENT group and 3. 84 f o r the ENVIRONMENT SAME group. The compar ison showed a s i g n i f i c a n t s e s s i o n s e f f e c t 41 F i g u r e 4. E l e c t r o d e p lacements o f r a t s i n the ENVIRONMENT DIFFERENT group and ENVIRONMENT SAME group from Exper iment 2. B r a i n s e c t i o n s mere taken from P e l l e g r i n o , P e l l e g r i n o and Cushman (1979). 43 F i g u r e 5. Mean t a i l — f l i c k l a t e n c i e s i n seconds f o r the ENVIRONMENT DIFFERENT and ENVIRONMENT SAME groups i n Exper iment 2. S e s s i o n 1 r e p r e s e n t s the t h i r d b a s e l i n e measurements! which were taken i n the c o l o n y room. S e s s i o n 2 r e p r e s e n t s the f i n a l b a s e l i n e measurements, which were taken i n the a l t e r n a t e environment. For s e s s i o n s 3-9, r a t s i n the ENVIRONMENT DIFFERENT group were a d m i n i s t e r e d b r a i n - s t i m u l a t i o n i n the a l t e r n a t e environment . F o r these s e s s i o n s , r a t s i n the ENVIRONMENT SAME 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 i n the c o l o n y room. On t e s t s e s s i o n s ( s e s s i o n s 10-13) a l l r a t s r e c e i v e d s t i m u l a t i o n s e s s i o n s i n the c o l o n y room. SESSION 45 CF(6, 96)= 19. 98, p < 0. 001), w i th no main e f f e c t f o r t reatment CF(1, 16) » 0.127, p > 0.53. By chang ing the s t i m u l a t i o n envi ronment from the s e p a r a t e room t o the c o l o n y room t o the c o l o n y room, the PAG s t i m u l a t i o n a g a i n produced an a n a l g e s i c e f f e c t , i n c r e a s i n g the mean t a i l - f l i c k l a t e n c y o f the ENVIRONMENT DIFFERENT group to 5. 57 sec . The e i g h t h c o n s e c u t i v e s e s s i o n o f s t i m u l a t i o n i n the c o l o n y room d i d not change the mean t a i l - f l i c k l a t e n c y o f the ENVIRONMENT SAME group, which remained at 3. 84 sec. A s i g n i f i c a n t s e s s i o n s by t rea tment i n t e r a c t i o n f o r s e s s i o n s 9-10 C F ( i , 16) = 10. 671, p < 0. 053 c o n f i r m e d t h i s e f f e c t . S i n c e the ENVIRONMENT SAME g r o u p ' s mean t a i l - f l i c k l a t e n c y i s i d e n t i c a l f o r s e s s i o n s 9 and 10, a l l o f t h i s i n t e r a c t i o n i s a t t r i b u t a b l e t o the i n c r e a s e i n mean t a i l - f l i c k l a t e n c y o f the ENVIRONMENT DIFFERENT group. T o l e r a n c e t o SPA was r e a q u i r e d i n the d i f f e r e n t group a f t e r f o u r s t i m u l a t i o n s e s s i o n s i n the new environment. T h i s i s c o n f i r m e d by a s i g n i f i c a n t s e s s i o n by t rea tment i n t e r a c t i o n f o r s e s s i o n s 10-13 CF(3, 16) = 3.67, p < 0.053. A Duncan 's M u l t i p l e Range t e s t CCd(64) = . 308k3 c o n f i r m e d s i g n i f i c a n t d i f f e r e n c e s f o r compar isons on s e s s i o n s 10, 11, and 12 (p < 46 D i s c u s s i o n The r e s u l t s o f the second s tudy demonstrate t h a t a change i n t e s t i n g envi ronment i s s u f f i c i e n t t o a t t e n u a t e t o l e r a n c e t o SPA. S u b j e c t s t e s t e d i n the same environment . as p r e d i c t e d . do not show t h i s a t t e n u a t i o n o f t o l e r a n c e . These r e s u l t s a r e taken as s u p p o r t f o r the s i t u a t i o n a l s p e c i f i c i t y o f t o l e r a n c e t o SPA. S i n c e i d e n t i c a l s c h e d u l e s o f s t i m u l a t i o n were ma in ta ined th roughout the exper iment . t h e o r i e s t h a t contend t h a t a d m i n i s t r a t i o n o f the agent i s s u f f i c i e n t t o produce t o l e r a n c e f a i l to p r e d i c t t h i s p a t t e r n o f data. The C o n d i t i o n i n g Theory o f t o l e r a n c e . on the o t h e r hand, m a i n t a i n s t h a t s i n c e c l a s s i c a l l y c o n d i t i o n e d r e s p o n s e s a re c o n t e x t dependent. t o l e r a n c e s h o u l d a l s o show c o n t e x t dependency ( S i e g e l . 1975, 1976. 1977). S e v e r a l i n v e s t i g a t o r s have demonstrated t h a t t o l e r a n c e t o m o r p h i n e ' s a n a l g e s i c e f f e c t i s g r e a t e r when s u b j e c t s r e c e i v e a l l i n j e c t i o n s i n the t e s t i n g environment . An ima ls t h a t r e c e i v e i n j e c t i o n s i n a d i s t i n c t envi ronment show a t t e n u a t e d t o l e r a n c e development (Advokat. 1981; Kayan. Woods & M i t c h e l l , 1969; S i e g e l , 1975, 1976; T i f f a n y & Baker, 1981). S i n c e S i e g e l c l a i m s t h a t f e a t u r e s o f the envi ronment s e r v e as the CS i t seems more a p p r o p r i a t e t o term the a t t e n u a t i o n o f t o l e r a n c e due t o a change i n envi ronment as a g e n e r a l i z a t i o n decrement, r a t h e r than c o n t e x t s p e c i f i c i t y . However. Bardo. Wellman & Hughes (1981) haves shown t h a t the f e a t u r e s o f the t e s t i n g a p p a r t u s seem t o be " p r e p o t e n t " as cues f o r c o n d i t i o n e d t o l e r a n c e . S i n c e the t e s t i n g appara tus remains c o n s t a n t th roughout t h i s exper iment , an argument can be made f o r l a b e l i n g the p r e s e n t r e s u l t s as c o n t e x t s p e c i f i c i t y . In e i t h e r 4 7 case , the p r e s e n t data s u p p o r t a r o l e f o r a s s o c l a t l o n a l p r o c e s s e s i n the a q u i s i t i o n o f t o l e r a n c e . As i n Exper iment 1, the data do not show complete a t t e n u a t i o n o f t o l e r a n c e . P h y s i o l o g i c a l mechanisms and b r a i n - s t i m u l a t i o n as a cue remain as p o s s i b l e e x p l a n a t i o n s . An a d d i t i o n a l p o s s i b i l i t y i s tha t , s i n c e the same t e s t i n g appara tus i s used (as w e l l as the same exper imentor ) , some CS g e n e r a l i z a t i o n may occur . A g a i n , the data p r e s e n t no c l u e s t o d i s t i n g u i s h between t h e s e p o s s i b i l i t i e s . 48 EXPERIMENT 3: HYPERALGESIC CONDITIONAL RESPONSE FROM PERIAQUEDUCTAL GRAY STIMULATION TOLERANT RATS A f t e r r e p e a t e d p a i r i n g s o f a CS and UCS. the CS, which i n i t i a l l y e l i c i t e d no response . o f t e n comes t o e l i c i t a CR (Pav lov . 1927). S i e g e l and h i s a s s o c i a t e s (Krank. H inson & S i e g e l , 1981; S i e g e l . 1975) p a i r e d d a i l y morphine i n j e c t i o n s ( e f f e c t i s UCS) w i th e n v i r o n m e n t a l cues (CS). S i e g e l ' s C o n d i t i o n i n g Model o f drug t o l e r a n c e r e q u i r e s the CR t o be a homeosta t i c compensatory mechanism, a n t a g o n i s t i c t o the a n a l g e s i c e f f e c t o f morphine. As a f u n c t i o n o f CS-UCS p a i r i n g s , the e n v i r o n m e n t a l CS comes t o e l i c i t the compensatory CR. The compensatory CR summates w i th the a n a l g e s i c a c t i o n o f morphine t o produce the a t t e n u a t e d drug e f f e c t t h a t d e f i n e s t o l e r a n c e . ( S i e g e l . 1975). When the e n v i r o n m e n t a l cues a re then f o l l o w e d by a p l a c e b o i n j e c t i o n , the compensatory CR i s m a n i f e s t as a h y p e r a l g e s i c response , r e l a t i v e t o s u b j e c t s r e c e i v i n g an a d d i t i o n a l i n j e c t i o n o r n o n i n j e c t e d c o n t r o l s ( S i e g e l , 1975). Groups w i th e q u i v a l e n t u n p a i r e d p r e t e s t exposure t o e n v i r o n m e n t a l cues and the drug have e l i m i n a t e d d i f f e r e n t i a l p r e t e s t assesment e x p e r i e n c e and e n v i r o n m e n t a l n o v e l t y as a l t e r n a t i v e e x p l a n a t i o n s f o r t h i s e f f e c t (Krank e t a l . , 1981). Compensatory CRs have a l s o been shown f o r the hypothermic ( S i e g e l , 1978) and locomotor (Mucha e t a l . , 1981) e f f e c t s o f morphine. C u r i o u s l y , S i e g e l ' s c o n d i t i o n e d h y p e r a l g e s i a has not been r e p l i c a t e d o u t s i d e h i s l a b o r a t o r y ( T i f f a n y e t a l . , 1983). C o n s i d e r i n g the many p a r a l l e l s between morphine a n a l g e s i a 49 and SPAi e n v i r o n m e n t a l cues t h a t have p r e v i o u s l y been p a i r e d wi th PAG s t i m u l a t i o n s h o u l d e l i c i t a h y p e r a l g e s i c response. Such a d e m o n s t r a t i o n i s c r i t i c a l t o a P a v l o v i a n i n t e r p r e t a t i o n of t o l e r a n c e t o SPA. Method S u b j e c t s . T h i r t y - f o u r male» Long-Evans r a t s were p r e p a r e d a c c o r d i n g to the methods d e s c r i b e d i n Exper iment 1. An a d d i t i o n a l e i g h t r a t s were l e f t un implanted. At the end of the exper iment . an ima ls wi th e l e c t r o d e s were s a c r f i c e d and b r a i n s removed f o r h i s t o l o g i c a l examinat ion . Apparatus . A l l appara tus were i d e n t i c a l t o t h a t used i n Exper iment 1. The t e s t i n g room was the o n l y environment. The temperature o f the water bath, however, was lowered t o 48. 5 C. T h i s was done t o i n c r e a s e b a s e l i n e t a i l - f l i c k l a t e n c i e s and a v o i d a " f l o o r e f f e c t " . Procedure . As i n the p r e v i o u s exper iments . b a s e l i n e t a i l - f l i c k measurements were r e c o r d e d over f o u r d a i l y s e s s i o n s w i th the f i r s t t h r e e measurements taken i n the c o l o n y room and the f o u r t h measurement i n the s e p a r a t e t e s t i n g environment . F o r t h i r t y o f the imp lan ted a n i m a l s . s e s s i o n s proceded e x a c t l y as i n Exper iment 1 through the t o l e r a n c e development phase. S i x t e e n an ima ls exceeded the c r i t e r i o n o f a two sec i n c r e a s e over b a s e l i n e t a i l - f l i c k l a t e n c y a f t e r i n i t i a l t rea tment w i th b r a i n - s t i m u l a t i o n . Four teen a n i m a l s d i d not meet t h i s c r i t e r i o n and were e x c l u d e d from the exper iment . The rema in ing f o u r i m p l a n t e d an ima ls and the e i g h t un implanted an ima ls s e r v e d as a n o n s t i m u l a t e d c o n t r o l group (NS-CONTROL). Ra ts i n t h i s 50 group r e c e i v e d seven s e s s i o n s of cue exposure f o l l o w e d by a t a i l - f l i c k t e s t , c o r r e s p o n d i n g t o the t o l e r a n c e phase. The t o l e r a n c e phase o f the exper iment was f o l l o w e d by a s i n g l e t e s t s e s s i o n . H a l f o f the s t i m u l a t e d r a t s (n=8) r e c e i v e d an a d d i t i o n a l s t i m u l a t i o n s e s s i o n (S-CONTROL). The rema in ing s t i m u l a t e d r a t s (n=8) r e c e i v e d a " p l a c e b o " s t i m u l a t i o n s e s s i o n f o l l o w e d by a t a i l - f l i c k t e s t (HYPERALGESIA). F o r an ima ls i n the HYPERALGESIA group the s e s s i o n was i d e n t i c a l t o s e s s i o n s i n the t o l e r a n c e phase, except t h a t the s t i m u l a t i o n l e a d s were d i s c o n n e c t e d from the s t i m u l a t o r . T h i s a l l o w e d p r e s e n t a t i o n of the c o n d i t i o n a l e n v i r o n m e n t a l cues w i thout s t i m u l a t i o n . The NS-CONTROL group r e c e i v e d an a d d i t i o n a l t a i l - f l i c k t e s t s e s s i o n . R e s u l t s H i s t o l o g y . A l l but two p lacements e l i c i t i n g a n a l g e s i a were found t o have e l e c t r o d e s i n , o r b o r d e r i n g on, the PAG. A l l p lacements not e l i c i t i n g a n a l g e s i a were w i t h i n o r b o r d e r i n g on the PAG. P lacements o f the f o u r i m p l a n t e d c o n t r o l s were a l l w i t h i n the PAG (F ig . 6). There was no apparent p a t t e r n o f d i f f e r e n c e s between p lacements e l i c i t i n g a n a l g e s i a and those p lacements not e l i c i t i n g a n a l g e s i a . S t i m u l a t i o n Produced A n a l g e s i a . D e c r e a s i n g the water ba th temperature t o 48. 5 C had the e f f e c t o f r a i s i n g b a s e l i n e mean t a i l - f l i c k l a t e n c i e s t o 7. 78 sec , 8. 62 sec , and 7. 02 sec f o r the HYPERALGESIA, S-CONTROL, and NS-CONTROL groups, r e s p e c t i v e l y (F ig . 7, s e s s i o n 1). S t i m u l a t i o n of the PAG i n c r e a s e d the mean t a i l - f l i c k l a t e n c y o f the HYPERALGESIA group t o 15. 82 sec and the S-CONTROL group to 17. 22 sec. By the s e v e n t h s t i m u l a t i o n s e s s i o n 51 F i g u r e 6. E l e c t r o d e p lacements o f r a t s i n the HYPERALGESIA group, S-CONTROL group and i m p l a n t e d NS-CONTROL group an ima ls from Exper iment 3. B r a i n s e c t i o n s mere taken from P e l l e g r i n o , P e l l e g r i n o and Cushman (1979). 53 F i g u r e 7. Mean t a i l - f l i c k l a t e n c i e s i n seconds f o r the HYPERALGESIA, s t i m u l a t e d c o n t r o l (S-CONTROL), and n o n s t i m u l a t e d c o n t r o l (NS-CONTROL) groups i n Exper iment 3. S e s s i o n 1 r e p r e s e n t s the f i n a l b a s e l i n e measurements. On s e s s i o n s 2-8, the HYPERALGESIA and S-CONTROL groups were exposed t o e n v i r o n m e n t a l cues f o l l o w e d by b r a i n - s t i m u l a t i o n . The NS-CONTROL group were exposed t o e n v i r o n m e n t a l cues but were not s t i m u l a t e d . On s e s s i o n 9, r a t s i n the HYPERALGESIA group were exposed t o the e n v i r o n m e n t a l cues, but were not s t i m u l a t e d . Rats i n the S-CONTROL group were g i v e n an a d d i t i o n a l s t i m u l a t i o n s e s s i o n . Rats i n the NS-CONTROL group were a g a i n exposed t o e n v i r o n m e n t a l cues , but were not s t i m u l a t e d . The m i s s i n g v a l u e f o r the NS-CONTROL group on s e s s i o n 6 (-) r e p r e s e n t s an equipment m a l f u n c t i o n . SESSION 55 (F ig . 7. s e s s i o n 8). mean t a i l - f l i c k l a t e n c i e s had d e c r e a s e d t o 9. 30 s e c i n the HYPERALGESIA group and 9. 28 sec i n the S-CONTROL group. A c r o s s t h i s same seven day p e r i o d . r e p e a t e d t a i l - f l i c k t e s t i n g d i d not a f f e c t mean l a t e n c i e s o f the NS-CONTROL group. A mean t a i l - f l i c k l a t e n c y o f 9. 41 sec d i d not s i g n i f i c a n t l y d i f f e r from the s e s s i o n 1 mean o f 7. 02 sec Ct(7) = 2. 32. p > .053. There i s . however, a t r e n d toward i n c r e a s e d t a i l - f l i c k l a t e n c y over r e p e a t e d t e s t i n g . A p l a c e b o s t i m u l a t i o n s e s s i o n d e c r e a s e d the mean t a i l - f l i c k l a t e n c y o f the HYPERALGESIA group t o 5. 82 sec , s i g n i f i c a n t l y below t h a t g r o u p ' s mean f o r both the p r e v i o u s s e s s i o n CDuncan's Cd(25, 4) = 1. 92, p < . 053 An a d d i t i o n a l s t i m u l a t i o n s e s s i o n d i d not change the S-CONTROL g r o u p ' s mean l a t e n c y (X = 10.74) . A t h i r t e e n t h c o n s e c u t i v e t a i l - f l i c k s e s s i o n d i d not change the NS-CONTROL g r o u p ' s mean l a t e n c y (X = 7. 9 s e c ) . A Duncan 's m u l t i p l e range t e s t c o n f i r m e d s i g n i f i c a n t d i f f e r e n c e s between s e s s i o n 9 s c o r e s f o r the HYPERALGESIA group and both the S-CONTROL [Cd(254) = 1. 89, p < . 053, and the NS-CONTROL CCd(25) = 2. 00, p < . 053. D i s c u s s i o n The r e s u l t s o f Exper iment 3 s u p p o r t the p r e d i c t i o n t h a t i n r a t s 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 o f PAG s t i m u l a t i o n , exposure to c o n d i t i o n a l e n v i r o n m e n t a l cues f o l l o w e d by a p l a c e b o s t i m u l a t i o n s e s s i o n s h o u l d r e v e a l a h y p e r a l g e s i c compensatory CR. In t h i s exper iment , r a t s exposed to e n v i r o n m e n t a l cues, but not g i v e n a s t i m u l a t i o n s e s s i o n , were more s e n s i t i v e t o a thermal 56 s t i m u l u s than both a group g i v e n an a d d i t i o n a l s t i m u l a t i o n s e s s i o n , and n o n s t i m u l a t e d c o n t r o l s . The n o n s t i m u l a t e d c o n t r o l group e l i m i n a t e s r e p e a t e d e x p e r i e n c e wi th the t e s t i n g p r o c e d u r e as an a l t e r n a t i v e e x p l a n a t i o n f o r t h i s e f f e c t (Bardo & Hughes. 1978; Hayes & Mayer. 1978; Sherman. 1979). These f i n d i n g s s u p p o r t the c o n t e n t i o n t h a t t o l e r a n c e t o SPA r e p r e s e n t s the summation o f the a n a l g e s i c e f f e c t o f the s t i m u l a t i o n and a homeosta t ic compensatory response . A l though Exper iments 1 and 2 s u p p o r t the i d e a t h a t t o l e r a n c e to SPA i n v o l v e s a s s o c i a t i v e p r o c e s s e s . Exper iment 3 p r o v i d e s e v i d e n c e f o r a homeosta t ic compensatory r e s p o n s e t o an e n v i r o n m e n t a l CS. T h i s d e m o n s t r a t i o n i s c r i t i c a l t o a P a v l o v i a n i n t e r p r e t a t i o n o f t o l e r a n c e t o SPA. As p r e v i o u s l y s t a t e d , S i e g e l ' s d e m o n s t r a t i o n o f a compensatory CR t o m o r p h i n e ' s a n a l g e s i c e f f e c t has not been r e p l i c a t e d o u t s i d e h i s l a b o r a t o r y ( T i f f a n y e t a l . , 1983). T h e r e f o r e , a l t h o u g h a n a l g e s i c agents d i f f e r , Exper iment 3 r e p r e s e n t s the f i r s t independent d e m o n s t r a t i o n o f a h y p e r a l g e s i c CR. The e x i s t e n c e o f drug p r e p a r a t o r y CRs s u g g e s t s a common mechanism f o r t o l e r a n c e and dependence (Krank, H inson & S i e g e l , 1981; S i e g e l , i n p r e s s ) . When an organism i s exposed t o cues t h a t p r e d i c t drug a d m i n i s t r a t i o n , i t may "prepare" i t s e l f f o r p h a r m a c o l o g i c a l a s s a u l t ( ie . e x h i b i t compensatory CRs). S i e g e l (1979) and Hinson and S i e g e l (1980) have sugges ted t h a t c o n d i t i o n a l compensatory r e s p o n s e s may account f o r many symptoms o f the a b s t a i n a n c e syndrome. An u n d e r s t a n d i n g of the 57 d e t e r m i n a n t s o f compensatory CRs may e v e n t u a l l y l e a d to t reatment programs f o r the r e l i e f o f t h e s e symptoms f o r p a t i e n t s undergoing drug wi thdrawal . 58 GENERAL DISCUSSION The r e s u l t s o f the p r e s e n t exper iments suppor t the p r e d i c t i o n t h a t t o l e r a n c e t o SPA, l i k e t o l e r a n c e t o m o r p h i n e ' s a n a l g e s i c e f f e c t / i s mediated by a P a v o l v i a n a s s o c i a t i o n a l mechanism. S p e c i f i c a l l y * t h e s e exper iments s u g g e s t t h a t SPA t o l e r a n c e i s the r e s u l t o f a c l a s s i c a l l y c o n d i t i o n e d homeosta t i c compensatory response . a n t a g o n i s t i c t o the a n a l g e s i c e f f e c t o f the s t i m u l a t i o n . The homeosta t i c CR summates wi th SPA t o produce the observed r e d u c t i o n i n a n a l g e s i a . Exper iment 1 demonstrated t h a t 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 o f PAG s t i m u l a t i o n can be e x t i n g u i s h e d . Repeated p r e s e n t a t i o n o f e n v i r o n m e n t a l cues a s s o c i a t e d wi th SPA a t t e n u a t e s the a n a l g e s i c e f f e c t o f the s t i m u l a t i o n . A t i m e - d e l a y c o n t r o l group shows no such decrement. P r e v i o u s exper iments ( S i e g e l . 1975. 1977) found t h a t e x t i n c t i o n t r i a l s a t t e n u a t e d t o l e r a n c e t o m o r p h i n e ' s a n a l g e s i c e f f e c t . N i e t h e r o f t h e s e r e s u l t s can be e x p l a i n e d by n o n a s s o c i a t i v e t h e o r i e s o f t o l e r a n c e , t h a t h o l d t h a t the a d m i n i s t r a t i o n o f a drug i s s u f f i c i e n t t o d e v e l o p t o l e r a n c e . They are . however, p r e d i c t e d by t h e o r i e s t h a t p r o v i d e a r o l e f o r l e a r n i n g i n the development o f t o l e r a n c e . Exper iment 2 p r o v i d e d e v i d e n c e t h a t the development o f t o l e r a n c e t o SPA i s c o n t e x t s p e c i f i c . A change o f t e s t i n g environment was s u f f i c i e n t t o a t t e n u a t e an e s t a b l i s h e d t o l e r a n c e . S e v e r a l l a b o r a t o r i e s have demonstra ted the c o n t e x t s p e c i f i c i t y o f t o l e r a n c e to morphine a n a l g e s i a (Advokat, 1980; S i e g e l , 1975, 1977; T i f f a n y & Baker, 1981). T h e o r i e s o f t o l e r a n c e t h a t 59 m a i n t a i n 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 o f the a n a l g e s i c agent i s s u f f i c i e n t to produce t o l e r a n c e cannot e x p l a i n t h i s e n v i r o n m e n t a l s p e c i f i c i t y . S i n c e c o n d i t i o n a l r e s p o n s e s are , i n many c a s e s , t i e d t o the envi ronment i n which they a r e formed (eg. Dweck & Wagner, 1970, M a r l i n , 1982), the c o n d i t i o n i n g t h e o r y o f t o l e r a n c e p r e d i c t s the e n v i r o n m e n t a l s p e c i f i c i t y o f t o l e r a n c e . A c r i t i c a l t e n e t o f the C o n d i t i o n i n g Theory o f drug t o l e r a n c e i s t h a t t o l e r a n c e r e f l e c t s a h o m e o s t a t i c CR. Exper iment 3 demonstrated a h y p e r a l g e s i c r e s p o n s e f o r SPA t o l e r a n t r a t s t h a t a r e p r e s e n t e d wi th an e n v i r o n m e n t a l CS. With the morphine a n a l g e s i a paradigm, S i e g e l and h i s c o - w o r k e r s (Krank, H inson & S i e g e l , 1981; S i e g e l , 1975) have shown c o n d i t i o n a l compensatory CRs u s i n g a p a w - p r e s s u r e a n a l g e s i o m e t e r and h o t p l a t e t e s t . T h i s e f f e c t has not been r e p l i c a t e d by o t h e r s ( T i f f a n y et. a l . , 1983) u s i n g the f l i n c h / j u m p shock t e s t . D e s p i t e the d i f f e r e n c e i n a n a l g e s i c agents , Exper iment 3 r e p r e s e n t s the f i r s t independent d e m o n s t r a t i o n o f a h y p e r a l g e s i c CR. Only the C o n d i t i o n i n g Theory o f t o l e r a n c e p r e d i c t s t h i s r e s u l t . P h y s i o l o g i c a l t h e o r i e s do not a l l o w f o r a c o n d i t i o n a l , h y p e r a l g e s i c response. Together , these t h r e e exper iments p r o v i d e s t r o n g e v i d e n c e t h a t the C o n d i t i o n i n g Theory o f T o l e r a n c e i s a p p l i c a b l e t o the t o l e r a n c e t h a t d e v e l o p s to SPA. I n t e r p r e t a t i o n o f c o n d i t i o n e d t o l e r a n c e a c c o r d i n g t o the s t i m u l u s - s u b s t i t u t i o n model proposed by S i e g e l (1975) has proved awkward. The o c c u r e n c e o f CRs i n the o p p o s i t e d i r e c t i o n , as w e l l as i n the same d i r e c t i o n as the UCRs can not be e x p l a i n e d by t h i s model. T h i s i s s u e has been 60 s p e c i f i c a l l y a d r e s s e d by E ike lboom and Stewart (1982). These au thors propose t h a t CRs o p p o s i t e i n d i r e c t i o n to the UCR can be e x p l a i n e d by d i s t i n g u i s h i n g between drugs t h a t a c t on an afferent arm o f a r e g u l a t o r y feedback system, and drugs t h a t a c t on an efferent arm, r e l a t i v e t o a c e n t r a l i n t e g r a t o r . They argue t h a t drugs hav ing an e f f e c t on an afferent or s e n s o r y arm o f the nervous system show c o n d i t i o n a l r e s p o n s e s i n the same d i r e c t i o n as the u n c o n d i t i o n a l e f f e c t o f the drug. In such a s i t u a t i o n , the drug i s c o n s i d e r e d to be the UCS and i t s e f f e c t the UCR. C o n v e r s e l y , drugs t h a t have an e f f e c t on an e f f e r e n t arm o f the nervous system show a CR i n the o p p o s i t e d i r e c t i o n t o the drug e f f e c t . In t h i s case , s i n c e the d i r e c t drug e f f e c t i s not d e t e c t e d by a c e n t r a l i n t e g r a t o r , the drug cannot be c o n s i d e r e d as a s t i m u l u s . I f a r e g u l a t o r y feedback i n t e g r a t o r d e t e c t s the d r u g - i n d u c e d change, then t h i s change i s c o n s i d e r e d t o be the UCS, and the r e g u l a t o r y r e s p o n s e i s the UCR. E ike lboom and Stewart (1982) propose t h a t t h e r e i s s u f f i c i e n t e v i d e n c e t o use t h i s model as a p s y c h o p h a r m a c o l o g i c a l t o o l . S p e c i f i c a l l y , agents showing CRs i n the same d i r e c t i o n as the drug e f f e c t s h o u l d have t h e i r e f f e c t on the i n p u t s i d e o f a r e g u l a t o r y i n t e g r a t o r , whereas agents showing a compensatory CR a f f e c t the output s i d e . A c c o r d i n g t o t h i s model, SPA s h o u l d be thought o f as a P a v l o v i a n c o n d i t i o n i n g t r i a l , w i th the a n a l g e s i c e f f e c t o f the s t i m u l a t i o n as the UCS, and a h o m e o s t a t i c compensatory response , a n t a g o n i s t i c t o the e f f e c t o f the s t i m u l a t i o n ( i . e. h y p e r a l g e s i a ) , would then s e r v e as the UCR. E n v i r o n m e n t a l cues t h a t p r e d i c t the s t i m u l a t i o n would be the CS, 61 and a compensatory mechanism the CR. On the b a s i s o f E ike lboom & S t e w a r t ' s arguments, t e n t a t i v e a n a t o m i c a l and p h y s i o l o g i c a l i n t e r p r e t a t i o n s can be made o f c o n d i t i o n e d t o l e r a n c e t o SPA. There i s e v i d e n c e t h a t PAG s t i m u l a t i o n a c t i v a t e s one o r both o f two b u l b o s p i n a l i n h i b i t o r y pathways (Watkins et. a l . , 1982). One o f t h e s e pathways i s a d i r e c t c o n n e c t i o n between the PAG and the s u b s t a n t i a g e l a t i n o s a o f the s p i n a l c o r d (Johannesson et . a l . » 1982; Watkins et. a l . , 1982). The o t h e r i s r e l a y e d th rough the NRM (Bebehanni & Pomeroy, 1978). The consequent i n c r e a s e i n ou tput o f t h e s e i n h i b i t o r y , b u l b o s p i n a l , efferent systems would, i n t u r n , cause a d e c r e a s e i n the f i r i n g r a t e o f the s p i n o r e t i c u l a r a f f e r e n t neurons. I t i s t h i s e f f e c t o f the s t i m u l a t i o n t h a t s h o u l d be seen as the UCS. A r e g u l a t o r y i n t e g r a t o r would d e t e c t a mismatch between s e n s o r y i n p u t and " s e t p o i n t " i n p u t ( p o s s i b l y d o r s a l column a f f e r e n t s , which s h o u l d not be a f f e c t e d by i n h i b i t o r y e f f e r e n t s ) and produce compensatory ou tput ( the UCR). P o s s i b l e s u b s t r a t e s f o r t h i s homeosta t i c mechanism i n c l u d e a decrease i n the f i r i n g r a t e o f e i t h e r or both o f the b u l b o s p i n a l i n h i b i t o r y systems or a c t i v a t i o n o f an, as ye t , u n i s o l a t e d e x c i t a t o r y e f f e r e n t system. E v i d e n c e f o r e x c i t a t o r y modu la t ion o f n o c i c e p t i v e a f f e r e n t s has r e c e n t l y been found (Larson , 1983). A t r y p t a m i n e r g i c system, a n t a g o n i s t i c t o i n h i b i t o r y s e r o t o n e r g i c neurons, may s e r v e as a " h y p e r a l g e s i c " modula tor i n the s u b s t a n t i a g e l a t i n o s a o f the s p i n a l cord . With r e p e a t e d p a i r i n g s , env i ronmenta l cues may come t o e l i c i t a decrease i n output o f the i n h i b i t o r y pathway, or an i n c r e a s e i n output o f the 62 e x c i t a t o r y pathway. E ike lboom and S t e w a r t ' s model o f c o n d i t i o n e d d r u g - i n d u c e d p h y s i o l o g i c a l r e s p o n s e s a l l o w s two p o s s i b i l i t i e s f o r the s t r u c t u r e o f the r e g u l a t o r y feedback loop. F i r s t , i t a l l o w s the i n t e g r a t o r to be l o c a t e d w i t h i n a c l o s e d feedback l o o p , w i th the PAG e f f e r e n t t o the i n t e g r a t o r ( F i g . 8a). In t h i s case the n e u r o a n a t o m i c a l data would sugges t t h a t the i n t e g r a t o r may be l o c a t e d between the pr imary n o c i c e p t i v e a f f e r e n t s and the s t i m u l a t i o n s i t e . T h i s may i n c l u d e synapses i n the tectum, b u l b a r r e t i c u l a r f o r m a t i o n , and PAG i n t e r n e u r o n s ( K e l l y . 1981). An a l t e r n a t i v e p o s s i b i l i t y would a l l o w the i n t e g r a t o r t o be l o c a t e d i n the s p i n o t h a l a m i c a x i s w i th the h o m e o s t a t i c r e s p o n s e mediated hormona l ly th rough the CSF. F o r example, b e t a - e n d o r p h i n c o n t a i n i n g neurons have been l o c a l i z e d i n the m i d - l i n e s t r u c t u r e s o f the thalamus. c o n t i n u i n g t o the PAG ( C u e l l o . 1983). B e t a - e n d o r p h i n i s r e l a t i v e l y s t a b l e i n the CSF (Weissman & Meshulam. 1983). I f t h e s e neurons a re found t o be a c t i v a t e d by p a i n f u l s t i m u l a t i o n and t h i s i s accompanied by a r i s e i n CSF b e t a - e n d o r p h i n . then the p o s s i b i l i t y o f a l o n g - l a s t i n g s p i n o t h a l a m i c a l l y - m e d i a t e d a n a l g e s i a system would be suppor ted . A n a l g e s i c agents s h o u l d i n d u c e a d e c r e a s e i n a c t i v i t y o f t h i s system. In t u r n , a d e c r e a s e i n CSF b e t a - e n d o r p h i n s h o u l d be c o n d i t i o n e d w i th r e p e a t e d SPA or morphine i n j e c t i o n . I f the i n t e g r a t o r were l o c a t e d efferent t o the s t i m u l a t i o n , w i t h i n a c l o s e d l o o p , t h i s model would demand an a n a l g e s i c CR. As t h i s was not observed , such a l o c a t i o n f o r the i n t e g r a t o r can be d i s c o u n t e d . 63 F i g u r e 8. P o s s i b l e l o c a t i o n s o f the " i n t e g r a t o r , " r e l a t i v e t o the PAC. In (A), the i n t e g r a t o r l i e s w i t h i n a c l o s e d loop , w i th feedback a t t e n u a t i n g i n p u t t o the PAC. T o l e r a n c e would be seen as a c o n d i t i o n e d i n h i b i t i o n o f e x c i t a t o r y i n p u t t o the PAG. In (B). the i n t e g r a t o r l i e s on a feedback l o o p t h a t i s d i s t i n c t from the P A G - s p i n a l c o r d a n a l g e s i a system. The mechanism t h a t i s c o n d i t i o n e d may be e i t h e r a d e c r e a s e i n output o f a p a r a l l e l i n h i b i t o r y system ( s o l i d l i n e ) or an i n c r e a s e i n ou tpu t o f an e x c i t a t o r y . " h y p e r a l g e s i a " system (broken l i n e ) . 65 The second case a l l o w e d by the E ike lboom and Stewart model would l o c a t e the s t i m u l a t i o n on an e f f e r e n t pathway d i s t i n c t from the r e g u l a t o r y feedback l o o p (F ig . 8b). In t h i s case i t would be p o s s i b l e f o r the PAG s t i m u l a t i o n t o affect d i r e c t s p i n a l i n h i b i t o r y e f f e r e n t s i which i n d u c e feedback through the NRM. A l t e r n a t i v e l y , i t i s p o s s i b l e t h a t i t i s the PAG-NRM c o n n e c t i o n t h a t i s s t i m u l a t e d and the r e g u l a t o r y feedback l o o p r e t u r n s through the PAG. In t h i s case the i n t e g r a t o r c o u l d be l o c a t e d anywhere w i t h i n the feedback loop. I f the d o r s a l column a f f e r e n t s , which f e e d the NRM through the M e d i a l Lemniscus and p o s s i b l y by d i r e c t i n p u t ( F i g . 1) a re seen as p r o v i d i n g i n f o r m a t i o n f o r the s e t p o i n t , i t becomes l i k e l y t h a t the NRM i s the i n t e g r a t o r , w i th PAG s t i m u l a t i o n e x c i t i n g a d i s t i n c t e f f e r e n t i n h i b i t o r y system. R e p l i c a t i o n o f the p r e s e n t exper iments u s i n g NRM and M e d i a l Lemniscus e l e c t r o d e p lacements may s e r v e t o e l u c i d a t e / c o n f u s e these i s s u e s . I f the NRM i s , indeed , the l o c a t i o n of the i n t e g r a t o r , b imoda l r e s u l t s c o u l d be expected w i th e l e c t r o d e s i n t h i s area. P lacements efferent to the r e l e v a n t synapses s h o u l d show compensatory c o n d i t i o n i n g ( i . e. t o l e r a n c e ) , whereas a f f e r e n t p lacements s h o u l d show the o p p o s i t e ( i . e. c o n d i t i o n e d r e v e r s e t o l e r a n c e o r s e n s i t i s a t i o n ) . I f d o r s a l column a f f e r e n t - M e d i a l Lemniscus neurons modulate s e t p o i n t , then s t i m u l a t i o n o f the M e d i a l Lemniscus s h o u l d produce a h y p e r a l g e s i c response , w i th no a n a l g e s i a . S i n c e the M e d i a l Lemniscus would be on the i n p u t s i d e o f the i n t e g r a t o r , r e p e a t e d s t i m u l a t i o n s h o u l d produce c o n d i t i o n a l h y p e r a l g e s i a . A t h i r d p o s s i b i l i t y i n t h i s case i s tha t a n a l g e s i a r e s u l t i n g from PAG s t i m u l a t i o n i s 66 a n t a g o n i z e d by d i r e c t a c t i v a t i o n o f a h y p e r a l g e s i a system (F ig . 8b/ broken l i n e ) . A major o b s t a c l e t o d e l i n i a t i o n o f b i o c h e m i c a l s u b s t r a t e s o f c o n d i t i o n e d t o l e r a n c e development has been the m u l t i p l e e f f e c t s o f p h a r m a c o l o g i c a l agents and d i v e r s i t y o f r e c e p t o r l o c a l i z a t i o n . The SPA paradigm appears t o p r o v i d e a s u i t a b l e s o l u t i o n t o t h i s problem by d e m o n s t r a t i n g c o n d i t i o n e d t o l e r a n c e i n a r e l a t i v e l y i s o l a t e d system. U s i n g the d e s i g n o f Exper iment 3/ b i o c h e m i c a l compar isons o f b r a i n and s p i n a l c o r d r e g i o n s b e f o r e and a f t e r exposure t o c o n d i t i o n a l e n v i r o n m e n t a l cues may y i e l d a g r o s s p i c t u r e o f t r a n s m i t t e r s i n v o l v e d i n the development o f c o n d i t i o n e d t o l e r a n c e . S p e c i f i c a l l y / a d e c r e a s e i n s p i n a l c o r d s e r o t o n i n m e t a b o l i t e s f o r HYPERALGESIA group, r e l a t i v e t o CONTROL group r a t s mould p o i n t towards a c o n d i t i o n e d d e c r e a s e i n NRM output as the CR. A d e c r e a s e i n s p i n a l n o r e p i n e p h e r i n e o r n o r e p i n e p h e r i n e m e t a b o l i t e s would s u g g e s t a c l o s e d c i r c u i t w i th a decrease i n d i r e c t P A G - s p i n a l ou tput as the CR. An i n c r e a s e i n t r y p t a m i n e would s u g g e s t a c o n d i t i o n e d i n c r e a s e i n a c t i v i t y o f a p u t a t i v e h y p e r a l g e s i a system (Larson , 1983). The c o n t e x t s p e c i f i c i t y d e s i g n (Exper iment 2) would d i s c r i m i n a t e between t o l e r a n c e due t o c o n d i t i o n i n g and p o s s i b l e p h y s i o l o g i c a l mechanisms. D i f f e r e n c e s i n t r a n s m i t t e r and m e t a b o l i t e l e v e l s o f s u b j e c t s i n the ENVIRONMENT SAME and ENVIRONMENT DIFFERENT groups, a f t e r exposure t o c o n d i t i o n a l cues, c o u l d be a t t r i b u t e d to env i ronment -dependent f a c t o r s . An u n d e r s t a n d i n g o f the b i o c h e m i c a l mechanisms i n v o l v e d i n the compensatory CR may l e a d to symptom r e l i e f s t r a t e g i e s i n the 67 treatment o f drug a d d i c t s e x p e r i e n c i n g a b s t a i n a n c e syndrome. For example, i f a c o n d i t i o n a l d e c r e a s e i n a s e r o t o n i n e r g i c i n h i b i t o r y mechanism i s shown t o be the s u b s t r a t e o f the h y p e r a l g e s i c CR, a d m i n i s t r a t i o n of a s e r o t o n i n a g o n i s t may r e l i e v e the " h y p e r s e n s a t i v i t y " e x p e r i e n c e d d u r i n g o p i a t e wi thdrawal . I t would a l s o be advantageous t o e x p l o r e the mechanisms i n v o l v e d i n development o f c o n d i t i o n e d t o l e r a n c e . L e s i o n s t u d i e s . f o r example. have s u g g e s t e d the invo lvement o f the p r e f r o n t a l c o r t e x (Ka lan t et. a l . 1978) and dopaminerg ic systems ( B l a s i g et. a l . . 1975) i n the development o f t o l e r a n c e to o p i a t e s . D e f i c i t s i n t o l e r a n c e development r e s u l t i n g from l e s i o n s i n t h e s e a r e a s have been a t t r i b u t e d t o the l o s s o f t o l e r a n c e - r e l e v a n t o p i o i d r e c e p t o r s . R e c e n t l y , s e v e r a l au thors have sugges ted t h a t t h e s e d e f i c i t s may be a t t r i b u t a b l e to damage i n a s s o c i a t i o n a l c i r c u i t r y r a t h e r than a hardwi red t o l e r a n c e system. S h o u l d s i m i l a r l e s i o n s produce an a t t e n u a t i o n o f c o n d i t i o n e d t o l e r a n c e i n the r e l a t i v e l y i s o l a t e d SPA system, a r o l e f o r l o c a l o p i o i d r e c e p t o r s would seem tenuous. F i n a l l y , an u n d e r s t a n d i n g o f the s u b s t r a t e s o f c o n d i t i o n e d t o l e r a n c e may l e a d t o drug t rea tment reg imens t h a t min imize t o l e r a n c e development by b l o c k i n g a s s o c i a t i o n s th rough p h a r m a c o l o g i c a l m a n i p u l a t i o n s o f r e l e v a n t c e l l p o p u l a t i o n s . The apparent d e m o n s t r a t i o n o f C o n d i t i o n e d T o l e r a n c e to SPA i s un ique because i t shows t h i s phenomena i s a r e l a t i v e l y i s o l a t e d system. More i m p o r t a n t l y , t h i s paradigm seems to be w e l l s u i t e d to p h y s i o l o g i c a l and b i o c h e m i c a l a n a l y s i s of the s u b s t r a t e s o f C o n d i t i o n e d T o l e r a n c e . 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