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The effects of morphine on the hypothalamo-neurohypophyseal system Ngsee, Johnny Kuan 1979

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91 THE EFFECTS OF MORPHINE ON HYPOTHALAMO-NEUROHYPOPHYSEAL  THE SYSTEM  by JOHNNY KUAN NGSEE B.Sc. , t h e U n i v e r s i t y  of British  Columbia,  A THESIS SUBMITTED IN PARTIAL THE REQUIREMENTS FOR MASTER OF  THE  FULFILMENT.OF DEGREE OF  SCIENCE  in THE FACULTY  OF GRADUATE  STUDIES  (Department o f P h y s i o l o g y )  We a c c e p t to  this  thesis  the required  THE UNIVERSITY  as  conforming  standard  OF BRITISH COLUMBIA  September  1976  1979  (c) J o h n n y Kuan Ngsee, 1979  In p r e s e n t i n g  this  thesis  in p a r t i a l  fulfilment of  an advanced degree at the U n i v e r s i t y of B r i t i s h the L i b r a r y s h a l l I  f u r t h e r agree  for  scholarly  by h i s of  this  written  make i t  t h a t permission  It  for financial  i s understood that gain s h a l l  Physiology  The U n i v e r s i t y o f B r i t i s h 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5  Date  I agree  r e f e r e n c e and  f o r e x t e n s i v e copying o f  permission.  Department of  for  Columbia,  this  October 11, 1979  Columbia  not  for  that  study. thesis  purposes may be granted by the Head of my Department  representatives. thesis  freely available  the requirements  or  copying o r p u b l i c a t i o n  be allowed without my  ii  ABSTRACT  (1mg/kg) rats  The  acute  of  morphine  produced  accompanied decrease  Brattleboro trait*  The  sulfate  a pronounced  by  in  a d m i n i s t r a t i o n of  an  water  in  was  dose o f v a s o p r e s s i n . homozygous  clearance  synthesizing  Since  vasopressin,  mediated  by  pressure  was  arterial  pressure  other  these  the  i t  decreased  was  the  in  both  morphine-mediated  In  stimulus  are  addition,  To were r e n d e r e d means:  study  multiple  acute  resulted (RIA),  found  mean  account rats.  In  the  possible  decrease  in  se  act  may  the for  vasopressin  effects  physically and  of  and  urinary as  a  morphine, r a t s  dependent  pellet  In c o n t r a s t t o t h e  chronic  a vasopressin  t h a t r a t s implanted  by  implantation  antidiuretic  administration,  i n p o l y u r i a . Using  i t was  blood  after  of  chronic  injections  morphine  can  of be  the  release  per  the  release.  t o l e r a n t and  morphine s u l f a t e . of  the  that  i t i s quite  hypotension  f o r vasopressin  arterial  D.I.  f o r the  in  must  animals,  responsible  and  incapable  immediately  This  a  exogenous  a l s o observed  homozygous  h e t e r o z y g o u s D.I.  hypotension flow.  the  and  insipidus  o f an  found  sharply  i n a l l animals.  that  diabetes  When  was  normal  r a t s are  mechanism(s).  monitored,  antidiuresis  the  antidiuresis  morphine i n j e c t i o n  n o r m a l and  in  A n t i d i u r e s i s was  hydrated  osmolality  comparable t o t h a t  D.I..rats.  and  dose  response. This  urine  r a t s heterozygous f o r the response  analgesic  to conscious  antidiuretic  increase  free  an  two of  effects treatment  radioimmunoassay with  a  morphine  iii  pellet  for  3  neurohypophyseal n=6)  days store  as compared  (1024. 1 ± 66.0 the  animals  withdrawal also  n=6).  This depletion  was  tolerance  the  a  to  physically  significant  ng  (n=6).  with morphine p e l l e t s ,  In  no  those  injected  with  from  the  detectable  i n these  changes i n the  abstinence  dependence  animals also  3  revealed  significant  sitas  rats  ( q ) . The  control  value  of  morphine-injected the  presence  Moreover, the  was  The  withdrawn  oxytocin  i i d n o t have any  in  of  on  direct  i t i s unlikely  hr  physical  whole  brain  morphine f o r 2 weeks  was  to  of  22. 37  the  binding  augmented  c h a n g e s i n g and  the drug  24  light.  (Kd)  to  any  withdrawal  after  degree  with  nM  restored  from  produce A  nM Kd  o f morphine i n t h e whole b r a i n Kd  rats  observed  d i d not  performed  constant 5.33  rats.  to  ng  changes i n  c h a n g e s i n t h e number  animals  b i n d i n g . Thus,  the  injected  affinity  were  monitored  i s very  H-naloxone binding of  no  that  animals  homogenate  the  902.4 ± 37.0  vasopressin stores.  suggested  i n these  animals  morphine f o r 2 weeks..Withdrawal  symptom, r e d u c t i o n i n body w e i g h t , of  abrupt  of  significant  vasopressin stores  drug  drug..  contrast  the neurohypophyseal daily  controls  dependent  - from  ng,  r e p l e n i s h e d as  depletion  vasopressin stores  lower  ± 27.9  implanted  638. 3 ± 36.0  implanted  (744.3  vasopressin  t h e d r u g from  neurohypophyseal  significantly  placebo p e l l e t  developed of  to  of  a  to the  ng,  produced  (n=6)  had  from in  a  the  suggested  homogenates.  control  value  in  f o r 24  hr. V a s o p r e s s i n or  effect  on t h e  that  the  3  H-naloxone  facilitation  of  iv  morphine  tolerance  m e d i a t e d by t h e i r  by  direct  the  neurohypophyseal  a c t i o n on t h e o p i a t e  peptides receptor.  is  V  TABLE OF CONTENTS  Abstract  i i  L i s t o f Tables  . ii  L i s t o f Figures  viii  v  L i s t of Abbreviations  ................................ .  Acknowledgements.  ................................. . x i  v  Introduction I.  ........................................  Effects  II.  o f A c u t e Morphine  Effects  of Chronic  A. I n d u c t i o n  A d m i n i s t r a t i o n ......  Morphine A d m i n i s t r a t i o n ...  of  T o l e r a n c e and  Chronic C.  to  Studies Morphine  III.  and  Tolerance  .............  AVP and  6  7  10 10  Memory t o  and Dependence ........  Objectives of the Current  5  With  Mechanisms o f T o l e r a n c e  Linking  1  P h y s i c a l Dependence  t h e Endogenous O p i a t e s  D. B i o c h e m i c a l E.  Associated  Morphine A d m i n i s t r a t i o n .........  Tolerance on  Changes  1  Physical  Dependence ............................... B. P h y s i o l o g i c a l  x  Study .............  12 17  Methods  19  I.  19  II.  Acute Morphine Experiments Chronic  Morphine Experiments .................  I I I . .Extract ion o f the Neurohypophyseal Peptides IV.  Opiate  .  Receptor B i n d i n g ......................  V. Radioimmunoassay  (RIA) o f V a s o p r e s s i n  .........  21 22 23 24  vi.  VI.  Radioimmunoassay  (RIA) o f O x y t o c i n  ............  Results I. II.  32  Acute E f f e c t s Chronic A. .The  Of  Effects  Morphine  ......................  Of Morphine  C . Serum O s m o l a l i t y D. Discussion  II.  Opiate Receptor  and  AVP  Chronic  o f Morphine  Effects  39 43  .....  51  .............  52  ..................  Administration  ......  o f Morphine A d m i n i s t r a t i o n  ...  ..........................................  Bibliography  32  ......  of Oxytocin  Sodium  Binding  Of  ..........................................  Acute E f f e c t s  Conclusion  ...................  Neurohypophyseal Stores  B. N e u r o h y p o p h y s e a l S t o r e s  I.  31  .........................................  55 59 59 65 75 77  vii  Table  I, E f f e c t s  on Mean A r t e r i a l  LIST OF  TABLES  of  S i n g l e Dose  a  Pressure,  U r i n e Flow  o f Morphine And  Urine  Osmolality Table  37  I I . The  Stores  Hypothalamic  o f AVP  in  the Multiple  T a b l e I I I . . Serum O s m o l a l i t y the P e l l e t Table  Implantation  IV..Number  Binding  and  and  Injection Serum  Series  Sodium  46  in  Series  of H-naloxone 3  Neurohypophyseal  54 Binding Sites  and  Affinity.................................  58  LIST OF  Figure  FIGURES  1. . C h r o m a t o g r a p h y  Sephadax Figure  C-25  of  1 2 5  I-AVP  on  CM  ....................................  2. C r o s s - r e a c t i v i t y  (a)  of  the  Antiserum  GP-13 Figure  28 3.  Cross-reactivity  (b)  of  the  Antiserum  GP-13 Figure  29 4..Renal  Morphine Figure  Morphine  on  Figure  on  and  Effects  in  Body  of  35 Effects  of  r a t ...............  Weight  During  Weight, Water  36  Chronic  o f Morphine .................... i n Body  33  of  rat  Cardiovascular  a Homozygous D.I  8. .Changes  Effects  Rat . . . . . . . . . . . .  Cardiovascular  and  injection  Urine Output  Long-Evans  a H e t e r o z y g o u s D.I  7. Changes  i . p.  Cardiovascular  a Normal  6. . R e n a l  Morphine  Figure  on  and  5.,Renal  Figure  26  Intake  r a t s I m p l a n t e d With M o r p h i n e  40  and  Pellets 41  Figure in Figure in Figure  9. .Changes  i n Body  the M u l t i p l e  Injection  10.  i n Body  ^..Neurohypophyseal Implantation  During Withdrawal  S e r i e s ................  Weight  the P e l l e t Implantation  Pellet Figure  Changes  Weight  During  Withdrawal  S e r i e s ..............  Stores  of AVP  in  Stores  45  the  Series  12.. H y p o t h a l a m i c  44  48 of  AVP  in  the  Pellet Figure the  Implantation  S e r i e s .......................  13. _ N e u r o h y p o p h y s e a l Pallet  Implantation  Figure  14. . S t e r e o s p e c i f i c  Figure  15. , S c a t c h a r d  naloxone  Plot  Stores  of Oxytocin  in  S e r i e s ..................  Binding of  of H-naloxone .... 3  Steoreospecific  50  3  53 56  H-  B i n d i n g .................................  57  X  L I S T OF  ACTH ADH AVP AVT CEzO Ci CNS Cos CSF D.I. fmol g GFR hr i.p.. kg LVP M M. A. P. mCi mEq mg min ml mM mmol mOsm ng nM pM Pos RBF RIA ul V  ABBREVIATIONS  a d r e n o c o r t i c o t r o p h i c hormone a n t i d i u r e t i c hormone arginine vasopressin arginine vasotocin f r e e water c l e a r a n c e curie c e n t r a l nervous system osmolar clearance cerebrospinal fluid diabetes insipidus fentomole gram glomerular f i l t r a t i o n rate hour intraperitoneal kilogram l y s i n e vasopressin molar mean a r t e r i a l pressure millicurie milliequivalent milligram minute milliliter millimolar millimole milliosmole nanogram nanomolar picomolar plasma o s m o l a l i t y r e n a l blood flow radioimmunoassay microliter u r i n a r y flow r a t e  ACKNOWLEDGEMENTS It  i s  Dr..N. W i l s o n , this Mr.  my  pleasure  f o r her i n v a l u a b l e  p r o j e c t . I would a l s o l i k e B. T i b e r i i s  to  thank,  my  advice  and i n t e r e s t i n  t o thank  supervisor,  Dr. , R . , K e e l e r and  f o r t h e many h e l p f u l d i s c u s s i o n s .  1 INTRODUCTION  I.  E f f e c t s o f Acute Morphine The  opiate  acute a d m i n i s t r a t i o n  agonists  behavioral,  has  drowsiness, euphoria, decrease (2,3). waxy it  in  flexibility  to  aspect  the  dependence,  be  depression.  stimuli in  in  non-narcotic  analgesics,  side  development  endocrine or  of  pain.  morphine the  the pain  In  has a  subjective  threshold (5).  effects,  of  and  (4) . C l i n i c a l l y ,  however,  tolerance  and  most  physical  of r e s p i r a t i o n . systems  stressful the  (6).Altered  are  known  stimuli.. ACTH-cortisol  endocrine  to  be  The;classic axis  in  states are also  associated  with  certain  changes  in  status  mood,  such  anxiety  and  alter  i t  or is  conceivable  as that  t h e mood o r t h e p e r c e p t i o n  psychoactive of p a i n f u l  by t h e a n i m a l would l e a d t o c o r r e s p o n d i n g  endocrine  of  marked  catatonia  alleviation  undesirable  Hence,  which  feeling  v a s o d i l a t i o n and a  as w e l l as r a i s i n g  to stress  to  a variety of  a  the  painful  psychological  drugs  produces  i t produces a s t a t e o f  i s the a c t i v a t i o n of  response known  morphine  and t h e d e p r e s s i o n  by  other  g a s t r o i n t e s t i n a l and e n d o c r i n e  i n experimental animals  Several  example  exert  selective e f f e c t i n diminishing  has s e v e r a l  altered  to  and  m o t i l i t y o f t h e g a s t r o i n t e s t i n a l system  most  of pain  notably  o f morphine  known  peripheral  i s used e x t e n s i v e l y  relatively  It  the  In a d d i t i o n ,  contrast  been  cardiovascular,  (1,2). I n man,  effects  Administration  status.  These  changes,  however,  changes are not  2  predictable  at present.  For  example,  e x p e c t e d t o have an i n h i b i t o r y view  of  stress.  i t s ability  endocrine Both  of  It  pituitary  by t h e a c u t e  with  the  drug  testicular  f u n c t i o n i n t h e male  and  resulted  has a l s o been r e p o r t e d  by  (15).  other  morphine. (10,12-14)  administration  effect  g o n a d o t r o p h i n s , FSH  treatment  morphine  and p r o l a c t i n  had an i n h i b i t o r y  be  o f p a i n and  (7-9). . S e v e r a l  ACTH  (7,10,11)  were s t i m u l a t e d  drug..  cycle  the p e r c e p t i o n  e v i d e n c e h a s shown t h a t  release  hormone  would  on ACTH s e c r e t i o n i n  s y s t e m s were shown t o be a f f e c t e d  secretion  the  the  growth  the  t o block  Yet experimental  stimulated  effect  morphine  of  on t h e . r e l e a s e o f (15).,  LH  Chronic  i n the a l t e r a t i o n of Irregular  menstrual  i n human f e m a l e d r u g  addicts  (16). M o r p h i n e h a s a l s o been antidiuretic  (17-20).  agent  morphine p r o d u c e d  a  water-loaded  ethanol  studies the  and  (17-20)  detectable  anesthetized  f o r example,  of  the  (19).  of  an  This  suggested  exercised  in  the  mg/kg,  effect f  on  Several  effect  by de Bodo  implicated the  opiate  that  potent  to  (21).  was shown t o be a b o l i s h e d by involvement  system..  antagonist, the onset  the  mediated through o p i a t e r e c e p t o r s . be.  antidiuretic  initially  was shown t o p r e v e n t  This  a  (17).  rats  hypothalamo-neurohypophyseal  administration nalorphine,  (21).  be  antidiuretic  have a s c r i b e d t h i s  neurohypophysectomy  to  At d o s e s as low as 0.4  r e l e a s e o f AVP, as p r o p o s e d  Antidiuresis,  shown  action Caution,  interpretation  of  such  Prior as  of a n t i d i u r e s i s of  morphine i s  however, these  must  studies.  3  Factors  a f f e c t i n g urinary  controlled These  and  have  factors  antidiuretic direct  not  been  included  o f t h e drug  Although  morphine  rat  water-loaded of  morphine  physiological  period  when  the  and  a  predominant  with  of  morphine  to  was  of  to  given  the  dependent  and t h e s t a t e  (22) .  given  t h e same dose  be  pulmonary  diuresis  antidiuresis..Thus,  appeared status  is  In p a t i e n t s  ( 2 3 ) . However,  r a t produced  changes  the  o f morphine h a s been shown t o  a  D i u r e s i s was a l s o o b s e r v e d  of  function.  antidiuresis  produced  poorly  eliminated.  potentiation  on r e n a l  the a d m i n i s t r a t i o n  hydropenic  conclusively  the  c a u s e d i u r e s i s i n some c a s e s . edema,  have, by f a r , been  a c t i o n o f AVP, c a r d i o v a s c u l a r  effect  response,  output  a  to a  effects  upon  the  of  the  hydration  animal. Antidiuresis factors. can  may  be  brought  on by a number o f  F o r example, c h a n g e s i n the c a r d i o v a s c u l a r  cause  a sharp  decrease  i n urinary  flow.  This  p r o b a b l e i n view o f t h e p o w e r f u l c a r d i o v a s c u l a r morphine  ( 2 4 - 2 7 ) . I n c o n s c i o u s human  subjects,  dose o f m o r p h i n e was shown t o i n d u c e  peripheral  arteriolar  vasodilation  (24)..  significant  decrease i n  systemic  function blood be  pressure  responsible  addition, of  c a n be d r a s t i c a l l y  AVP  in  blood  for  the  also  Most  i s highly e f f e c t s of a  15  mg  v e n o u s and  turn,  l e d to a  pressure.  Renal  a l t e r e d by c h a n g e s i n s y s t e m i c  ( 2 8 - 2 9 ) . Thus, h y p o t e n s i o n  i t may (30).  This,  system  decrease  serve studies  in  urinary  as a s t i m u l u s have  may  conceivably flow.  In  f o r the r e l e a s e  indicated  that  the  4  cardiovascular  e f f e c t s of  morphine a r e  ( 2 4 - 2 7 ) . T h i s , however, does not of  a peripheral  a c t i o n . Green  morphine i n c r e a s e d  the  turn  increase  led  to  formation  an  and  in  cavity^  The  resulting  directly  alter  release  of  conscious, to  a  the  and  in  RBF  hydrate  effect and  of the  GFR  was  morphine  rat  were  hypophysectomy antidiuresis However,  was  the  view of  experimental  the  the  rat,  the  c a u s e d by  same dose  given  produced  has the  reduction  low  experiment RBF  and  by  a  reduction (32)  by  de  in  Bodo  abolished  to conclude of  the  administration  not  l e d them  A  Keller  r e s u l t s presented  of t h e i r  abnormally  the  function.  a n t i d i u r e s i s was This  animal.  explained  dogs a f t e r the  be  in  rat  and  the  to  a l s o be  Handley  animals.  the  bradycardia.  by  validity  stimulate  and  observed  (32).  can  observed  renal  fluid  volume  In  ( 2 5 , 2 6 ) . The  in  peritoneal  appeared  anesthetized  hypophysectomized  that  This  o f c o n s c i o u s n e s s of the  on  found t h a t  as  (30).  drug  to  the  plasma  well  a n t i d i u r e s i s may  morphine. Contrary  (21) , t h e y  in  state  have shown  in  in  e f f e c t s , namely h y p o t e n s i o n  n o r m a l and of  to  possibility  r a t e of a s c i t e s  fluids  peptides  unanesthetized  Lastly, direct  the  tachycardia  chloral  opposite  of  response  upon  Hypertension  in  decrease  vasoactive  the  venous r e s i s t a n c e .  r e n a l f u n c t i o n as  cardiovascular dependent  exclude  e t a l . (31)  hepatic  pooling  mediated c e n t r a l l y  RBF is GFR  and  by that GFR.  questionable in  their  5  II.  Effects  of C h r o n i c  Prolonged  Morphine A d m i n i s t r a t i o n  treatment  with  a g o n i s t s has  been known t o i n d u c e  dependence  (33)..  development exposure. obtain  of  Tolerance  insensitivity  Thus, i n c r e a s i n g l y  the  Tolerance  effects  i s often assessed of  Physical  d e p e n d e n c e , on  altered  the  be  the  drug  and  state is  included  and  after  l o s s and  vocalization,  elevation of  occurrence  tolerance  and  concomitantly Writhing the  dependent  and  to  with  dog  syndrome.  dog  the  of  rat, this  weight  mainly  o f each  assessment  of  the  fact  symptom. the  abstinence These  degree  of  i s often a complicated  that  various  withdrawal  shaking,  the  on t h e i n c i d e n c e o f  of  dependence  (34).  the  a g r e s s i v e b e h a v i o r , body  increasing  predominant animals  In  an  teeth  precipitated  wet  prevent  constellation  signs.,  i s based  physical  to  continued  or abstinence a  use.  shaking,  and/or i n t e n s i t y  T h i s i s due  the  j  dependence  and  analgesic  refers  to  to  dose.  i t s repeated  hand,  wat  given  o f body t e m p e r a t u r e ^ A s s e s s m e n t  Quantitative tolerance  the  the  repeated  original  necessary  jumping,  as  upon  whereby  physiological  physical  must be  the  encompasses  hyperactivity,  chattering,  degree  syndrome  opiate  defined  doses  other  or  and  comparing  of a stereotyped withdrawal  behavioral  be  by  the  o f the drug  withdrawal  task.  can  with  before  physiological  administration  The  drug  tolerance  larger  observed  potency  onset  to  morphine  tolerance  do or  signs  of  not i n c r e a s e dependence.  f o r example, were shown t o signs signs  in  moderately  decreased  or  even  6  disappeared by  more  with  i n c r e a s i n g d e p e n d e n c e , and  vigorous  motor e x c i t a t i o n s u c h  M o r e o v e r , q u a n t i f i c a t i o n based o n l y may  not  be  adequate,  pre-treatment conceivably one  with  responsible  another drug.  sign  various  daily  it  is  due  the  level  of  the  drug  between  studies.  animal  if  the  dosage per  between  excretion by  the  d o s a g e and  that  pre-treated water  morphine  time  go  and  i s low  with  physically  than the  or  in  often  fact  that  induce  a  dosage  crucial  the  are  these  interval affect  and  often  the  urine  influenced  because  a time period  the  withdrawal  time  used,  clearance  in  of  may  and  much  such longer  drug.  Rats  m o r p h i n e were shown t o consume  food  and  shortly  the  major  o f the  voraciously  for  on  circulating  intake  schedule  made o v e r  to  the  i n turn  Water  mainly  p h y s i c a l dependence.  a period  which  variable.  required  and  ( 3 5 ) . One  are  through  long,  injection  mechanism  Dependence  required  fluctuation  may  may  underlying  basic  tolerant  measurements, f o r example,  measurements a r e than  of  injection  response  mechanism  Physical  injections  i n j e c t i o n s too  measured  pre-treatment  between i n j e c t i o n s . The  time i n t e r v a l The  made  tolerance  This  to  Such  and  the  of  sign  p h y s i c a l dependence. .  is  degree  be  specific  studies involving  procedure, other  reasonable  replaced  jumping ( 3 4 ) .  means. E a r l y s t u d i e s r e l i e d  this  laborious,  may  and  be  injection  disadvantage with  one  in  neural  of Tolerance  A n i m a l s can d e p e n d e n t by  the  as  without a f f e c t i n g the  for tolerance  hs. I n d u c t i o n  the  especially  i n t e r f e r e with  specific  on  were  after  a  morphine;injection..  7  Moreover, food the  effect  not hr.  and  of the  water i n t a k e drug  wore o f f  have been d e t e c t e d Therefore,  effect  of  a  and  steady  and  Tingstad  drug  i s to d e l i v e r the  (37)  method  over  to t h a t  of the  have been used  and  a very  Morphine  in  most  by  of  morphine.  Associated  Gibson  in  studies animals.  with  (38)  24  continuous  induced  injection  the  as  this  compared  With  Chronic  development of  tolerance  for  This  depression  has of  the  rate  elevated  in  t o l e r a n t and  respond  differently  Whereas  antidiuresis  animal,  simultaneously.  parameters  dependent  depressed  respiratory center  body  have  states  been shown t o be  and  were o f t e n  occur  example, was  pressure,  pulse  to  physiological  physically  rate, (40).  seem  of the  naive  be  time  decrease i n s e n s i t i v i t y  (42)  would  chronic  dependent  of  Changes  a  designed  period  dependence  in  persistently  on  extensively  animals, the  several  Respiratory  Moreover,  drug  the  as  Administration  physical  the  study  physically  short  multiple  For  to  These c h a n g e s  to  dependence can  B_. P h y s i o l o g i c a l  drug users  method  and  significantly  measurements made o v e r  ideal  tolerant  observed  were t h e  the  Maximal t o l e r a n c e  Changes  (36).  b a s i s . Morphine base p e l l e t s  requiring  and  decreased  (39,40). in  chronic  primarily center  t o CO2  and  a  single  were  also  dependent  (17-21)  and  s e e n a f t e r morphine p o l y u r i a and  morphine inhibition  animals..  the  often  injection. of  drinking  administration  p o l y d i p s i a are  the Blood  p h y s i c a l l y dependent animals  to  due  (41)..  temperature  physically  been  to  a  predominant  8  responses encountered (36,42-44). of  in  Studies balance are  on  the  examine t h e two  of  i n d u c i n g e x c e s s i v e water and  a  by  loss  will  to  morphine  water  to  sedative  and  have  been  thirst  is  On and  on  the  Salt  of  renal  by  drugs.  by  the  in a tolerant may  stimulated water apparent  been  and  due  a  to the  the a n i m a l  possibly  has  animal  may  effect  of  observed i n be  due  loss.  an  to  There  inhibitory  (17)..Thus,  a temporary  the  state  consumption.  metabolism nephrotoxic  narcotic  or  or i t s s e n s a t i o n of  S e v e r a l r e p o r t s have c i t e d  disease  the  of  have c a u s e d water  to  administration  polydipsia  morphine  whether  The  euphoric  may  cause  drug.  have  the  capable  thirst  t h e e x c e s s i v e water  that  and the  by  animals  diuresis  d e h y d r a t i o n and  narcotic  may  incapacitated  caused  release  water  complicated  by  the  o t h e r hand, the  dependent  AVP  link  due  of  e u p h o r i c e f f e c t s of the drug;  imbalance  resulting of  animal  evidence to suggest  effect  caused  after  have been masked  morphine.  water  naive  temporarily  may  tolerant  imbalance  drinking a  close  It is difficult  was  salt  morphine  water  v e r s a . Hence, i t i s not c l e a r  response  of  the  on  invariably  of the animal's p e r c e p t i o n  inhibition  use.  drug  excretion.  modification and  reversal  p r o c e s s e s i n d e p e n d e n t l y . A drug  vice  in  animal  a complete  of  complicated  intake:and urine  dependent  with repeated  effects  to  polydipsia,  t o be  of t h e d r u g  frequently  water  drinking  physically  Thus, t h e r e appeared  some o f t h e e f f e c t s  between  a  may  further  effect  of  be the  the c o e x i s t e n c e  addiction  (45-47).  The  9  statistical  evidence  and  existence  the  nephropathy  is  unequivocal  proof  capable of  causing  agents  range  from  Bichter  used  promote  the  to  muscle  acute renal originally  renal  rhabdomyolysis,  addicts  of  i s another i n drug  i t is  is  likely  not that  in  and p h o s p h a t e m e t a b o l i s m  likely  responsible  about t h e r e n a l  candidates  (53,54).  f o r rhabdomyolysis  r e m a i n t o be p r o v e n .  crush  the  (49) a s  i n kidneys  Bhabdomyolysis well  or  antigens on  adulterants  addicts  i n p a t i e n t s with failure  particle.  can a c t as  disease.  These  adulterants  (50) have been d e t e c t e d  to bring  most  to explain the  immunoglobulins  membrane.. Some  found  no  etiological  viral  that  the heroin  renal  i s  (45-50) .  ubiquitous  essential calcium  Various  suggested  necrosis  described  acute  drug  deposition  failure  There  by r e s e a r c h e r s  the  to dilute  with  heroin-associated  o r any o f t h e o p i a t e s a r e  failure.  in  as immunoglobulins  skeletal  specific  heroin  renal  basement  drug a d d i c t s  Since  that  disease  fari s controversial,  circumstantial.  e t a l . (48) have  glomerular  of  a  best  heroin  substances  well  at  of  have been i m p l i c a t e d  onset of r e n a l  and  a v a i l a b l e thus  or  known c a u s e o f (51). I t  was  syndrome ( 5 2 ) .  a common f e a t u r e o f other  factors  are  disturbance..Imbalance a r e among two The  of the  actual  mechanisms  following heroin  addiction  10  - Tolerance Endogenous  to  discovery  activity  act competitively  with  peptides  be used i n p l a c e  the  physical were  dependence. to  administration B-endorphin  be  of  and  level  is  regulate  their  viewed  as an a d a p t i v e  Several the  development  dependence  of  (59).  have s u g g e s t e d  due  to  target  cell.  shifts  i n the  serve  as  of  neural  and dependence  o r exogenous  a  may  excessive  opiates.  Tolerance  h y p o t h e s e s h a v e been p r o p o s e d t o e x p l a i n  (60)  the  endogenous  r e s p o n s e t o the  of the o p i o i d peptides Mechanisms  possible  a c t i o n s on s p e c i f i c  thus  Rs. B i o c h e m i c a l  repeated  The  may  and  peptides,  on t h e s e  The d e v e l o p m e n t o f t o l e r a n c e  influence  opioid  dependence  the  (57,58).  circuits. be  and by  peptides  receptor  tolerance  I t i s possible that to these  to  analgesic,  opioid  and dependence  not c l e a r .  to  endogenous  enkephalins  of r e s p o n s i v e n e s s  mechanism  evoked  with  been shown  these:  of  tolerance  easily  the  that  development  the  have  o f m o r p h i n e a s an  However,  advantage o f t o l e r a n c e peptides  expectations  impending  shown  the  question  morphine on t h e o p i a t e  were  without  high  These p e p t i d e s  (56). There may  on  o f endogenous p e p t i d e s  (55) posed an i n t r i g u i n g  drug a d d i c t i o n r e s e a r c h e r s . to  P h y s i c a l Dependence  Opiates  The r e c e n t opiate-like  and  morphine  Lampert  tolerance  and  physical  e t a l . (57) and C o l l i e r  t h a t t o l e r a n c e and dependence  alteration  of adenyl  et a l . . may  cyclase activity  M o r p h i n e and endogenous  opioid peptides  be  of the have  11  been  shown  possessing the  drug  inhibit  (62).  in  an  Thus,  This  cellular inhibitory  effect  stage, the  cells  o f morphine t o abrupt  are  account  of  and  to  with  of  the  level neuronal  the  high  drug  level  processes  normal  adenyl c y c l a s e coupled  for  animals.  (63,64).  the b e h a v i o r a l  intoxication enkephalin rats  and  has  (65).  were  and  reduction  of  dependence  in  the  of  has  (62)  i n the  can,  The  been  and CNS  may  during  therefore,  be  which h e l p t o r e g u l a t e t h e  Turnover altered  changes  rates in  observed  and  dependence  in  Hughes might  enkephalin  be  in  several dependent  t o be r e s p o n s i b l e  during  Elevated  a l s o been o b s e r v e d  of  physically  been t h o u g h t  withdrawal*  neuronal  an  s y n a p t i c communication.  T h i s has  Kosterlitz  tolerance  This  this  AMP.  result  AMP.  of the  o t h e r b i o c h e m i c a l c h a n g e s were n o t e d  neurotransmitters animals  the  presence  synthesis  of a c t i v i t y  regarded  dependent  of  to  of c y c l i c  hyperexcitability  and  Several  inhibitory  tolerant  and  to  a normal l e v e l  would  cyclic  withdrawal* .Tolerance as  to the  a d e n y l cyclase.„At  cyclase of  cells  adenyl  synthesis  appear on  of  d e p e n d e n t upon t h e c o n t i n u e d  adenyl  high  for  the  m a i n t a i n a normal l e v e l  disinhibition  associated  adapt  in  exposure  synthesis  to maintain  of morphine  withdrawal  abnormally  cells  them  AMP  Prolonged  enhanced  increasing  allows  cyclic  cyclase activity  (57,61).  the  o f m o r p h i n e by  enzyme.  adenyl  opiate receptors  resulted  cyclase effect  to  periods  levels  morphine (66)  of  brain  dependent  proposed  explained  of  by  r e l e a s e as t h e  that the normal  12  f u n c t i o n s of these opiate,  p e p t i d e s were r e p l a c e d by  morphine. M a l f r o y  suggested  that  the  e t a l . , (67)  increased  enkaphalia-degrading  peptidase  serves  and  dependence. Both thesa  symptoms  of  withdrawal  target  binding  control  in  s i t e s can  drug  (68).  of  In  a  considered  the  mechanism imply  of that  l a c k of a c t i o n  on  their  of the  opiate  the  site  of  of  respective  Tolerance  Aside tolerance  and  electrical  The  events  learning  the r e s p o n s i v e n e s s  to  pathways, of  to  the  of  drug  has  not  a  feedback  cycle.  The  receptor i s often action.  be  been r e p o r t e d by  Hence,  binding  or  excluded  Enhancement o f t h e  the as  a  number o f  P e r t and  Snyder  mice. , AVP  and  Memory t o  the  biochemical  changes,  dependence have been l i n k e d  t o the  stages.  of  step  r e c e p t o r can  or  Morphine-  Dependence  from  memory p r o c e s s e s according  step  linking and  number  ligand-recaptor  i n morphine-treated Studies  initial  control.  binding sites  E.  affinity  biochemical  molecule  initial  concentration principal  the  drug  in  the  hand,  high-affinity  hypotheses  neurons  receptor  most  alterations  two  other  a  to the  conceivably alter  i s e x e r t e d on  binding  (69)  as  exogenous  cells. Changes  a  a r e due  enkephalin-containing  the  l e v e l s of a  tolerance  the  on  the  of the animal  (70,71).  c u r r e n t dogma first  stage  to learning Memory  involves  Storage  at  least  alterations  processes  shortly  this  and  storage,  (72), c o n s i s t s of a t  and/or metabolic experience.  morphine  in  after  stage  is  13  temporary  and i s o f t e n  Long-term  memory  and  involves  is  accompanied  collaterals studies  i s  by  view o f t h i s , in  that  on memory  et a l .  9  development  (Brattleboro  and  (77)  morphine  have  strain)  but  morphine  tolerance  rats  also  impairment as  heterozygous l i t t e r m a t e s which  AVP  consolidation  and  (78).  AVP a f f e c t s  of protein  receptors.  a  memory  of  possible  Interactions  between e n d o c r i n e s y s t e m s documented  the to  memory  development  their  normal  biochemical  of or  mechanism  facilitate  memory  o f DG-LVP  processes  to  a m n e s i a (79) through  the  i n t h e CNS.  action  of  between  AVP  on  endocrine  the  CNS  (80-82). I t i s o f i n t e r e s t  hormone - AVP i n t h i s  chronic  facilitated  morphine:tolerance  and  and  AVP a n a l o g u e ,  puromycin-induced  metabolism  Facilitation m e d i a t e d by  in  In  h e r e d i t a r y D.I.  i s a s y e t unknown. The a b i l i t y  that  alteration  that  exhibited  i t s analogues  the animal against  suggested  only  The  of  plays a  tolerance  (DG-LVP),  compared  number  also  inert  In a d d i t i o n , not  o f axon  (74-76).  shown  vasopressin  8  This  i t s a n a l o g u e s have a  the peptide  of  of tolerance.  deficiency  protect  (73). A  o f mice w i t h a b i o l o g i c a l l y  desglycinamide -iysine  by  consolidation.  consolidation  development  dependence. K r i v o y  the  AVP  i t i s probable that  the  memory.  more permanent i n n a t u r e  connectivity  shown effect  short-term  m e t a b o l i c c h a n g e s , and growth  and n e u r a l  have  treatment  considered  a process of information  facilitating  role  r e f e r r e d t o as  have  may  a l s o be  the  s y s t e m s , and been  to speculate  c a s e - may m o d u l a t e  or  opiate  exert  well that a some  14  influence exert  on  the o p i a t e r e c e p t o r s . . A l t e r n a t i v e l y ,  i t s effect  release  of  ACTH.  potentiated analogues  on  by  interfere  The  AVP  have  the  oxytocin,  shown  with  also  AVP,  appeared  activity  C-terminal  was  ring  o f ACTH i s known t o ACTH  by  e t a l . (85)  Terenius  to f a c i l i t a t e  shown  the  its to  dependence  to reside  hormone,  development (86)  on  p r o - l e u - g l y - ( N H ) . Tocinamide, of  o x y t o c i n , was  found  the the  2  structure  of  Moreover,  predominantly  play a s i g n i f i c a n t  Although  role  these r a t s e x h i b i t e d  in an  the  to  be  Brattleboro  impairment  d e v e l o p m e n t o f morphine t o l e r a n c e ( 7 7 ) , t h e y  are  i n the capable  synthesizing oxytocin. Most  studies  neurohypophyseal their  and  nuclei  the  CNS,  knowledge o f t h e i r  selectively  being  presence  i n a l l the  in  taken  synthesized these  clear  nuclei  directed  at  CNS  are  and  their the  important.  i n various hypothalamic  whether t h e s e p e p t i d e s a r e  i n which t h e y  up by  were  detected  the hypothalamic  elsewhere..  nuclei  the  presence:  p e p t i d e s reach the  (87,88).,It i s not  are  been  of  In o r d e r t o understand  o x y t o c i n h a v e been f o u n d  synthesized  after  the p h y s i o l o g i c a l r o l e  p e p t i d e t h u s f a r have  r o u t e by w h i c h t h e s e AVP  on  extraneuronal actions.  a c t i o n s on  or  and  be  ( 8 6 ) . I t i s q u e s t i o n a b l e w h e t h e r o x y t o c i n and i t s  by-products  of  the  Furthermore,  physical  tripeptide,  N-terminal  rats.  through  the other neurohypophyseal  morphine t o l e r a n c e and  inactive  secretion  (83,84).  been  receptors  may  with the b i n d i n g o f the o p i a t e s t o the r e c e p t o r . As  this  opiate  AVP  suggests  neurons  Nevertheless, a possible  their  neuronal  15  connection  and/or f u n c t i o n . Neural  and/or o x y t o c i n  have been  out  from  the  of  the  b r a i n . . These  the  shown by  Buijs  p a r a v e n t r i c u l a r nucleus  amygdala and pathways  pathways c o n t a i n i n g  areas  various  behavioral  effects  of  the  nuclei.  t o be  the  the  to  axons  and  extrahypothalamic these  two  these  an  neurons  fibers  peptides  neurons.  exert  dendrites  Some  of  anatomical  peptides  in  effect  hormone,  effect  on  general  i d e a s emerging  neuronal  of  supraoptic  neurohypophyseal  oxytocin  f u n c t i o n as  Iontophoresis  the  the  AVP on  a  paraventricular  nucleus  from t h e s e  basis for  (86,90).  is  present  that in  has  shown  to  percentage  of  been  large (91). has  The: an  neurons  other  inhibitory (92). . AVP  The and  g e n e r a l r e g u l a t o r s of  membrane p r o p e r t i e s . I n c o n t r a s t t o the  neurotransmitters, their  in and  evidence  s t u d i e s are t h a t  a c t as n e u r o m o d u l a t o r s and  The  neurotransmitters  nucleus oxytocin,  these  hypothalamic  (89)., There  may  inhibitory  of  areas  hippocampus,  n e u r o h y p o p h y s e a l p e p t i d e s have been shown t o be both  spread  towards v a r i o u s  included  medullary  have been t h o u g h t  (89)  AVP  a c t i o n s appear t o  be  classical of  longer  duration. Aside  from  direct  n e u r o h y p o p h y s e a l hormones may the  CNS  via  the  morphological  neuronal be  cerebrospinal  evidence  of  transported fluid  cells  third  (93). T h i s suggested  that  and/or s e c r e t e d  the  may  be  taken  up  the  There i s  between  the  i n f u n d i b u l a r r e c e s s of  into  AVP CSF  the  throughout  (CSF) .  connections  neurosecretory ventricle  and  contact,  and from  the  oxytocin neuron  16  terminals.  Immune-reactive  Dogterom e t a l .  (94)  in  AVP  dog,  p r e s e n c e i n t h e CSF h a s been avoidance CSF  by  behavior the  antibodies  of avoidance  play  a  (96)  administration  r o l e i n modulating  various  With r e g a r d s  As  in  systemic  o f AVP i n CNS s t r u c t u r e s  imbalance  tolerance.  is  to  Thus,  neurotransmitter development  hypersecretion  Stimulation  circulation  m e t a b o l i s m . One method influence  of  promote the or  endocrine  to the hypothalamo-neurohypophyseal  endogenous o p i o i d p e p t i d e s unnecessary  most  some form o f f e e d b a c k  mechanism t o p r e v e n t t h e e x c e s s i v e  the  in  of  opioid  the  (97)..  endogenous o p i o i d p e p t i d e s .  the  Removal o f AVP i n t h e  endogenous  that  significant  system, t h e e l a b o r a t i o n  an  i n the c o n d i t i o n e d  behavior.  functioning requires  into  CSF. I t s  marked  systems, proper  a  rat  by  a  functions  as  and  detected  resulted  neuroendocrine  control.  been  implicated  o f the r a t (95).  T h e r e i s no d o u b t peptides  human  intracerebroventricular  AVP-specific reduction  has  influence of  AVP  by t h e p r e s e n c e  o r exogenous o p i a t e s  diminishing  such  t h e development  release  of  AVP  tolerance  and  o f AVP i n t o t h e s y s t e m i c  act  of the release  of excess may  i n the animal's s a l t  cause  and water  stimulative  of t a r g e t either  i n t o t h e CSF may s e r v e  of  may  as  cell a  to f a c i l i t a t e prevent  circulation.  the  17  III.  O b j e c t i v e s - of t h e C u r r e n t  The the  present experiments  effects  on  the  o f both  acute  from  the  antidiuretic  response  the state  of  animal.. In  the  was  this  The  hydrated  release  from  overcome  hypoosmolality.  rats  were  as e x c e l l e n t  release  and  encountered  with  the  use  antidiuretic  at  acute  e f f e c t s of  and  hydrated  osmolality  antidiuresis  i s mediated  then  the  effect  of  the role  of  the  with  familial  to  that  of  drug plasma  AVP  in  responses  of  hypothalamic  their  homozygous  normal  D.I. r a t s  Trauma  and t e c h n i c a l  these  response  can  animals.  The  i n the normal  rats  failure  o f t h e homozygous D*I. r a t s  would  conclusively  prove  that  thus  AVP  difficulties be  presence coupled  t o respond  and have  c o n t r o l s i n many s t u d i e s i n v o l v i n g  i n hypophysectomy  of  two  plasma  elucidate  The  least  of consciousness  (100)  actions.  often  in  inhibitory  litterraates.  was  known t o be i n h i b i t e d i n  antidiuresis,  compared  heterozygous served  is  decrease  To f u r t h e r of  the  It  morphine-induced  the neurohypophysis,  the  induction  Brattleboro D.I.  by  I f t h e morphine-induced  AVP s e c r e t i o n  the  governed  AVP  a n i m a l s o r by a  (98,99).  the  using unanesthetized  of  treatment  system.  that  study,  t o examine  morphine  o f h y d r a t i o n and l e v e l  morphine were examined  must  and c h r o n i c  literature  factors:  by  were d e s i g n e d  hypothalamo-neurohypophyseal  apparent  rats.  Study  avoided of to  an the  t o morphine  antidiuresis  i s  AVP  mediated. The  effects  of chronic  morphine treatment  on t h e  18  h y p o t h a l a m i c and n e u r o h y p o p h y s e a l studied..  Changes  radioimmunoassay these urine  with  animals  been  on  the  s t o r e s o f AVP  morphine.  made  due  to  i n t a k e and  in  physically  p r o v i d e some i n s i g h t  t o t h e mechanism  Studies  based  the  between  of the  neurohypophyseal  by  might  correlate  the d e p l e t i o n  Changes  the  on  the  facilitation  neurohypophyseal  exclusively There  e f f e c t s of chronic  of  to  by  water  on  the  morphine  hypothalamic shed the  some  of  peptides exogenous  i s no s t u d y t h u s f a r  hypothalamo-neurohypophyseal  measurement  interactions  were  also  determined  encountered  of these peptides.  on t h e p o s s i b l e  were  were  in  tolerance  application  be  AVP s t o r e s .  morphine t o l e r a n c e . .  (77,78) have  stores  animal's d a i l y  often  may  s t o r e s may a l s o  morphine  storage  the  output..Polyuria  neurohypophyseal  fo  AVP  (RI A) . A t t e m p t s  changes  dependent  AVP  in  AVP  and  light  administration system..  The  neurohypophyseal on  neurohypophyseal  the  possible  p e p t i d e s and  19  METHODS  1^ A c u t e -Morphine Male  Brattleboro  heterozygous  f o r the  (D.I.) t r a i t , Long-Evans rats  Experiments  strain,  right  carotid  cannulated  back o f t h e neck carotid  transducer  were  anesthetized  a  was c a n n u l a t e d Urine  held the then tip  samples  incision*  i n place  o f the catheter  injected  This l o c a l  rats,  i n c i s i o n and tubing  subcutaneously  with  to the  incision. a  pressure  on a u.v. r e c o r d e r (S.E.  infusion*  the  lateral  tail  a PE-10 t u b i n g . were  collected  was  a suture  by c a t h e t e r i z i n g  was e x p o s e d  opening  catheter  guided  the  e t h e r . The  PE-50  by  a  small  was made i n t h e apex and  i n s e r t e d . The c a t h e t e r was  and c a r e  was t a k e n t o m i n i m i z e  amount o f dead s p a c e i n t h e b l a d d e r . gently  The  with  was m o n i t o r e d  The b l a d d e r  A small  with  After was  using  bladder*  flare-tipped  from  control*  by a m i d l i n e  and r e c o r d e d  vein  a  as  was p a s s e d  L t d . ) . For intravenous  midline  rats  heparin-filled  pressure  (Statham)  urinary  insipidus  and b r o u g h t o u t t h r o u g h a s m a l l  blood  and  which t h e B r a t t l e b o r o  used  Lab.  the  male  from  a r t e r y was e x p o s e d with  diabetes  were  ( C l a y - A d a m s ) . The c a n n u l a  The  Normal  the strain  200-300 g,  homozygous  hypothalamic  were s t u d i e d .  were: d e r i v e d ,  weighing  rats,  The  bladder  was  back i n t o t h e a b d o m i n a l s p a c e w i t h t h e protruding  surgery,  2.5 mg o f M e p i v a c a i n e  subcutaneously  anesthetic  o u t the abdominal  was used  around in  incision. (Winthrop)  the i n c i s i o n  order  to  sites.  lessen  the  20  surgical  pain  which may s t i m u l a t e  a n i m a l was t h e n commencing rat  was  allowed  to  the release  recover  for  the experiment. A f t e r t h i s hydrated  with  infused  infusion  s o l u t i o n was s i m i l a r t o t h a t  Fujimoto  omitted  and a  samples  were  sulfate  intravenously  (17)  with  slower  collected  injected  into the t a i l  a  of  dose  given  only  flow  rate  the  at  exception rate  10  vein  that  ethanol  chosen*  in  weight. Morphine  as the percentage  excretion  rate  a f t e r morphine  The  urine  Osmolar  clearance  (Cos)  using  of  0.9%  NaCI  and  a  i n j e c t i o n s were constant  reduction  (Oos)  (Osmette, and f r e e  the following  Cos  Drine  urine  The r e s u l t s  in  the  urine  injection.  osmolality  depression  was  i n t e r v a l s . Morphine  a t l e a s t two c o n t r o l p e r i o d s *  point  Inturrisi  a t v o l u m e s o f 20-30 u l t o g i v e  were e x p r e s s e d  were c a l c u l a t e d  period, the  by  was  min  a f t e r the establishment  freezing  before  o f 51 u l / m i n . The  used  was d i s s o l v e d  1 mg/kg body  for  recovery  at a rate  infusion  (BDH C h e m i c a l s )  hours  a s o l u t i o n o f 0.3% NaCI and 1.6%  glucose,  and  2  o f AVP. The  was  measured  Precision  by  System).  water c l e a r a n c e  (CH2O)  formulae:  = Uos x V / Pos  C H 0 = V - Cos 2  Where V i s t h e u r i n e osmolality.  excretion  rate  and  Pos  the  plasma  21  iii  C h r o n i c Morphine Male  housed  Wistar  individually  were g i v e n  ad l i b .  12 h r l i g h t - d a r k The m o r p h i n e by  sulfate were  fourteenth group  injection*. the  withdrawal  a t 22° C with a  injection  Two  were  and  method,  (101).  doses The  space  pellet 24  rats  injected  o f morphine  control  rats  hour  after  injections group  will  be  morphine-treated their  daily  were w i t h h e l d  for  24  hr  referred  to  pellet 75  implantation  from  before as  mg  prepared  Tingstad  method,  morphine according  (37).  sulfate to  Thirty-six  the  the  After  two  days  of  housing,  with morphine p e l l e t s  under l i g h t  ether  groups  served  as c o n t r o l s  pellets  composed o f t h e i n e r t  (Allen method  in  four  The  of  metabolic were  subcutaneous  remaining  and were i m p l a n t e d  &  divided  groups  i n the dorsal  anesthesia.  morphine  r a t s were  6 e q u a l g r o u p s and p l a c e d i n d i v i d u a l l y  implanted  and  g r o u p s were  g r o u p and one  one  group  containing  Hanbury's);  cages.  d e p e n d e n t on  group. For the  into  water  an e q u a l volume o f 0.9% NaCI. On t h e  morphine  This  were  0700-1900 h r ) . .  with i n c r e a s i n g  f o r 14 days  g, and  physically  multiple  morphine-treated  sacrifice..  Gibson  (i.p,*)  with  Daily  on from  3 equal groups.  sacrificed  second  pellets  (light  day, t h e c o n t r o l  were  Food  the multiple i n j e c t i o n  twice d a i l y  injected  cages.  were r e n d e r e d  For  intraperitoneally  200-250  The room was m a i n t a i n e d  means:  into  weighing  i n metabolic  rats  implantation.  rats,  cycle  two  were d i v i d e d  Experiments  with  two  placebo  i n g r e d i e n t s . . S t u d i e s (33,34)  22  have shown t h a t  the  pellet  rapidly  decreased  plateau  after  3 days a f t e r constant  the f i r s t  delivery  One  was  morphine  a few  was  in  1,  was  5  pellets.  The  implanted placebo p e l l e t s  remaining  sacrificed  3  days  control after  Alteration  i n body w e i g h t  used  as an  index of p h y s i c a l  III.  Extraction  On  of the  previously  were s a c r i f i c e d into was  a  and  by  143).  After  - 2 0 ° C.  flame  by B i e and  tissues  (103), was  on  in  day  5.  implanted removed  groups of the  were  pellets.  period  was  (102). Peptides  the treated  b l o o d was  rats  collected  f o r 1 h r . The (1400  x g  clot  for  Serum o s m o l a l i t y  d e p r e s s i o n ( O s m e t t e ) , and (Instrumentation the  Lab.,  and  10 was  serum model  neurohypophysis  the adenohypophysis  hypothalamus,  Thorn  Trunk  decapitation,  s e p a r a t e d from The  dependence  a t - 2 0 ° C.  a  treatment.  withdrawal  allowed t o c l o t  photometry  the  the  d e s i g n a t e d days,  point  maintain  were a l s o  excision  speed c e n t r i f u g a t i o n  freezing  sodium  quickly  low  and  implanted  the  Both  Neurohypophyseal  t h e serum s t o r e d  measured by  The  tube  removed by  min)  during  by d e c a p i t a t i o n .  test  removing  group*  the  to  morphine-implanted  day  the  to  5 days of  one  surgically  was  sacrificed  on  tended  morphine-implanted  on  from  by  a  3 and  also  precipitated  pellet  each  examine the c h a n g e s  s t o r e s o f AVP, after  from  d a y s and  order  o f t h e d r u g . To  of the c o n t r o l groups  group  after  pellet  sacrificed  Withdrawal.  of  a week. Hence, a s e c o n d  the neurohypophyseal group  absorption  frozen  was at  a c c o r d i n g to the boundaries s e t removed  ( n e u r o h y p o p h y s i s and  and  frozen  hypothalamus)  at  -20°  C.  were t h e n  23  suspended (pH  i n 6-10  2.85)  at  300  6000  and  RPM x  g  M  acetic  for  sec. 30  The  min.  homogenate was The  l y o p h i l i z e d . The  pellet  acid  assembly  centrifuged  was  discarded  at  and  l y o p h i l i z e d powder was  the  stored  -20 ° C. .  H i  Opiate - Receptor Brains  saline  or  devoid  of  was  re-suspended  in  second time.  The  at 10  cerebellum  of  Folin-Lowry A  (pH  has  in  7.4)  sec.  of T r i s - H C l pellet  This 16.33  was  method  10  mg/ml  had  an  assay  and  aliquot  of  the  brain  homogenate, c o n t a i n i n g  1.5  mg  p r o t e i n , was  (New  England  brain  performed  in  Snyder  incubated at  17.15  binding  was  and  triplicate.  3  (106)  with  was  centrifuged in  was  2.33  nM  Ci/mmol)  at  determined  (Hoffman-LaRoche)  homogenate  pellet  5  similar  Pert  of l e v a l l o r p h a n  ice cold  ml  a of  protein  (n=22) as e s t i m a t e d  by  Non-specific  and  average  described  min.  removed  homogenate  The  suspended  be  of  The  and  to  by  (105) .  receptor-binding  Nuclear,  ml  min.  buffer  suspension ± 0.16  10  after  shown  i t was  homogenized f o r 30  with  removed  been  (104),  12,000 x g f o r  ml  chronically  quickly  activity  final  buffer.  concentration the  the  buffer  centrifuged  injected  were  Each b r a i n was  Tris-HCl  Tris-HCl  rats  morphine  receptor  discarded. mM  Binding  from  decapitation..Since  50  0.2  homogenized i n a P o t t e r - E h l v e j e h m  f o r 30  supernatant at  volumes o f i c e c o l d  to  the  that  used. A  100  of  3  H-naloxone  4° C  by  for  adding  All 60  ul  approximately  115  tubes c o n t a i n i n g  H-naloxone. After  to  min  assays  60 nM the  were  incubation  24  period,  the  glass-fiber 5 ml  samples filters  volunes of  partially  (24  under  overnight  Nuclear)..10  ml  added t o e a c h counted  in  of  a  absence*  binding  V.  known  to  used  i n the  Ind. )  was  acetic  Burget  (pH mCi  7.4). of  was  10  12.5j  reagents  (pH  stopped  by  the  protein  (New  England  Nuclear)  counter.  subtracting  presence  of  the  which o c c u r r e d in  a l t e r e d by the  the  to  the  opiate in  its  presence  adding  100  binding  showed  was  r a d i o a c t i v i t y was  by  binding  with  the  scintillation  from t h a t  not  was and  mM  of  that  the  bind  to  of  NaCI, opiate  amount  of  all  opiate  the  method  3.0)  u l of  Wilson a  AVP and  was 15  according  (108).  AVP  by  dissolved  u l of  were added react  a d d i t i o n of  (109)  Greenwood e t  0.5  M  100  to  f o r 50 u l of  (Eastman)  The BSA  the  (110). 0.05  M  buffer and  solution.  sec. 25%  r  of  phosphate  the  Med.  of  al.  i n 10 / i l  1 mg/ml c h l o r a m i n e - T  to  to  (Spectrum  modification  described  allowed the  Vasopressin  performed  by  (Amersham)  were  and  twice  f i l t e r s were  and  England  the  jRIA). o f  synthetic  acid  in  The  Protosol  determined  adequate  iodinated  of  washed  GF/B  tube.  c h l o r a m i n e - T method ug  vial  This  assay  by  ml  enhance  was  Radioimmunoassay  described  10  was  (107).  The  and  (New  non-specific  levallorphan receptors  1  was  levallorphan,  antagonists  t h r o u g h Whatman  lamp  (LS-233)  occurred  The  is  with  Omnifluor  excess i e v a l l o r p h a n which  infra-red  Beckman  which  antagonist^  diameter)  scintillation  Stereospecific binding  mm  filtered  ice cold Tris-HCl buffer.  dried  digested  were  1.5 The  reaction (Pentex).  25  In a d d i t i o n , 200 u l of Bio-Rad anion exchanger, AG1-X10 a t 250  mg/ml, was added to help  well  as  were  then  the  complex p o l y i o d i d e s .  removed  resulting  separated and  (pH  by  supernatant,  (9 x 800 mm)  bind the  purified  low-speed  centrifugation.  containing  the i o d i n a t e d  on  Sephadex  CM  first  to  e q u i l i b r a t e d with 0.6 M sodium acetate  buffer  e l u t i o n p r o f i l e of the i o d i n a t i o n mixture BSA  was  d e r i v a t i v e t o be e l u t e d from the column and i t to  the  antiserum  (GP-13).. T h i s  was  by s e v e r a l small r a d i o a c t i v e peaks corresponding  unreaoted  radioactive AVP,  AVP, was column  showed no b i n d i n g followed  The  C-25  4.85).. The  a  a s  The i o n exchange beads  on CM Sephadex C-25 i s shown i n f i g . 1. Iodinated the  1251  unreacted  followed  1251  a  n  d  derivative  complex to  be  polyiodides. eluted  by d i - i o d i n a t e d AVP.  The  next  was mono-iodinated  25a  FIGURE 1.  Chromatography column  (pH 4.85) fraction order  with  at  a  of  I-AVP  a  flow  n  M rate  o f 70  Q  mono-iodinated (d).  The  0.6  elution i2sj  on CM  mm)..  consisted  unreacted  AVP  2 5  (9 x 800  equilibrated  (b),  of i  was the AVP  Sephadex column  acetate  C-25 was  buffer  o f 18 m l / h r . Each  drops  (or 5 m l ) .  iodinated complex (c) and  BS A  The (a),  polyiodides di-iodinated  26  27  The  amount o f mono-  dependent (>45  sec)  on  and  the  favored  di-iodinated  reaction the  production  Standardized supplied  by  Torrance,  Dr.  preparation sodium The  of  antiserum  immunized  (GP-13) was  and  AVT  against  no  with  A VP  cross-reacted  45  pM  of  specific  against  region  at  AVP,  was  bounded  least  by  the the  the  of  This  oxytocin  (112)  preference  f o r AVP.  and  N - t e r m i n u s and disulfide  of  13 AVP  the  bridge.  of  pM  raised It  whereas  analogue,  i t cross-reacted  antiserum  populations  the  1:90,000.  was  An  pigs  antiserum  antiserum  also tested  two  by  a s s a y , the  pM.  3P-13  BSA  M  serum.  to  the  100  0.15  coupled  at a concentration at  the  from g u i n e a  a greater  ( f i g . 3 ) . Hence, t h e  consist  b u f f e r was  c r o s s - r e a c t i v i t y with  i t exhibited  in  normal r a b b i t  dilution  Although  Hospital,  obtained  In  AVP.  extract,  used  HIA  0.25%  (111).  a final  ( f i g . 2).  desamino-dicarba at  at  was  was  r e a c t i o n time  ( H a r b o r Gen.  The  s y n t h e t i c LVP  showed  LVP,  with  longer  more d i - i o d i n a t e d  IO/ml,  (GP-13) was  reaction  cross-reacted LVP  7.2)  used  used  antiserum  2.1  obtained  pituitary  Weitzman  standards.  (pH  against  carbodiimide  at  the  phosphate  of  posterior  Ri . E.  Calif.)  time..A  AVP  appeared  to  antibodies;  one  other  against  the  27a  FIGURE  2.  Inhibition GP-13  by  Oxytocin  of b i n d i n g the  of i  500  greater (•) .  I-AVP  to  neurohypophyseal  (o) and a r g i n i n e v a s o t o c i n  no i n h i b i t i o n o f b i n d i n g of  2 5  pM/L.  The  preference  up t o a  antiserum f o r AVP  (•)  antiserum peptides. (o) showed  concentration (GP-13) than  showed  for  LVP  28  28a  FIGURE 3.  Comparison and l 2 s  leu-enkephalin  I-AVP  from  analogue, lesser (•).  in  The  I-AVP.  o f an AVP  the  GP-13.. The  desamino-dicarba  endogenous  as  analogue  displacement  the antiserum,  cross-reactivity  enkephalin 1 2 S  of e f f e c t i v e n e s s  AVP  (o)  compared  opioid  of AVP  showed to  peptide,  (A) d i d n o t d e p r e s s t h e b i n d i n g  AVP leuof  o  BOUND / o  FREE  30  The l i m i t arbitrarily binding* of  defined  as  80%  T h i s i s more t h a n  initial  binding often  condition, (13.6  of detection  the l i m i t  o f t h e s t a n d a r d c u r v e was  of  the  the three  used  initial  o r maximal  standard  deviations  by o t h e r a u t h o r s . O s i n g  of detection  was about  13 f m o l  this  o f AVP  ± 1.9 f m o l , n=15), and 50% d i s p l a c e m e n t o f * I - A V P 2 5  occurred  a t 52 f m o l  (52.1 ± 3.6,  variation  at  50 f m o l  inter-assay  variation  n=15).  level  The  intra-assay  3.2%  was  u s i n g p o o l e d dog  (n=18).  plasma  was  The  13.9%  (n=15) . The dissolved the  lyophilized  i n t h e RIA b u f f e r .  posterior  pituitary  hypothalamic  tube  was 1.0 ml. The a s s a y Separation  accomplished dextran  T-70,  amount  25  of i  added v e r s u s t h e Linearization in  logit  of  and a  The  assayed  bound  and  Norit  A  was made f o r dilution  at  4° C  free  * I-AVP (2.5  charcoal  in  I-AVP  by t h e t o t a l  of  unlabelled  expressed  AVP  was done by e x p r e s s i n g t h e r e s p o n s e  (113).  mg/ml  0.15  were  logarithm  was  2 5  charcoal  bound d i v i d e d  for  for 3  pH 7 . 2 ) . The r e s u l t s 2 S  were  volume o f each RIA  was i n c u b a t e d  mg/ml  be  1:10  final  by u s i n g d e x t r a n - c o a t e d  phosphate b u f f e r , the  extract.  to  A 1:500 d i l u t i o n  extract  the  days.  tissues  M as  amount  present.. variable  31  ILs. Radioimmunoassay  Acetic the  pellet  oxytocin. (114).  cross-react  of  Oxytocin  acid extracts  implantation  The  The  (RIA)  RIA  used,  arginine  The  of d e t e c t i o n  of t h i s  oxytocin.  The  intra-  and  similar  that  of the  to  has  assay  or  assayed  for  previously to  vasopressins,  epinephrine  was  inter-assay  from  been shown not  lysine  I, c a l c i t o n i n  AVP  also  been d e s c r i b e d  and  angiotensin  neurohypophysis  were  SP-4,  vasotocin, limit  the  series  p r o c e d u r e has  antiserum with  of  about  25  (114). fmol  variations  radioimmunoassay.  of  were  32  RESULTS  ia. Acute E f f e c t s Of The  animals  intravenously was  Morphine were.  a hypotonic  infused  slowly  osmolality.  Urine  to  glucose-saline  p r e v e n t any  excretion  Once a s t e a d y u r i n e  at  least  two  was  i n j e c t e d i n t o the  dose,  1 mg/kg, was  antidiuresis rats. rat  min  An  i n the  hydrated the  i s shown i n f i g . 4. immediately  generally  lasted for  recovery  to  phenomenon recovery increase back t o  the was  phase.  changes i n  observed  rate  was  periods, cannula.  normal  response of The  to  a  the min  observed The  rate  in  D.I.  of u r i n e  low  i n a marked (Brattleboro)  normal  Long-Evans occurred  injection. . It was  a  gradual  r a t e . .A  rats  rebound  during  excretion  pre-injection level  for  sulfate  A moderately  there  several  plasma  obtained  morphine  morphine  and  This  increase  a n t i d i u r e t i c response  after 10-20  and  infusing  solution.  pre-injection excretion  beyond the baseline.  vein  by  c h o s e n . T h i s dose r e s u l t e d  example o f  almost  was  flow  collection tail  abrupt  rate  gradually.  10  hydrated  before  was  seen  the to  returning  32a  FIGUEE 4.  An  example  response single drug  of  of  a  dose  the normal  urinary  flow  period.  to  g  indicates Changes  body  clearance  after  in  rat  to  a  mean  Urinary  flow  weight.  arterial  Corresponding and  was  a  The  corrected  dashed  osmolality  t h r o u g h an  (Cos)  establishing  f o r a t l e a s t two 10 min  changes i n u r i n e  were m o n i t o r e d cannula.  Long-Evans  (MS)  collection 100  cardiovascular  (1mg/Kg) o f morphine s u l f a t e . The  was i n j e c t e d  steady  r e n a l and  (Uos).  pressure  (M.A.P.)  indwelling  carotid  changes  free  line  in  water  (CEUO) a r e shown i n t h e b o t t o m  graph.  osmolar clearance  34  The D.I.  rats,  comparable also  brief  to that  produced  the  have  recovered  in  caused  46%  (n=6)  observed  i n the  20  was  phenomenon  was  effect.  to  drug  and  of  morphine  on  arterial over  50%  n o r m a l r a t . The in  D.I.  than  min  appeared  of the  and  caused  the was  (n=6)  not  as  great  also  showed  reduction  in  of  (n = 6)  heterozygous  morphine i n j e c t i o n .  that  blood  same dose  d i f f e r e n c e was  rats  a f t e r the  groups.  sedative  effects  reduction  25%  less  morphine  effect  normal group, the  A  1 mg/kg o f  min.  i n the  this  observed  h e t e r o z y g o u s D.I.  urine  pre - i n j e c t i o n  however,  reduction  response.  significantly  of  c a t a t o n i c f o r 5-15  sedative  morphine  Homozygous  was  or  osmolality  flow  that  was  the  urine  group.. Although  excretion  to  noticeable  I summarizes t h e  urine  significant.  rats,  immobile  within  D.I.  antidiuretic  but  1 mg/kg,  reduction  Morphine  of a n t i d i u r e s i s  a rebound  Most a n i m a l s ,  from  excretion,  a  groups of  a mild  conscious  At  period  rate  were  rats.  injection.  Table  homozygous  f i g . 6,  i n the  subsequent r e t u r n  remained  after  pressure*  reduction  normal r a t s ,  a l l three  animals  urine  the  i n several  were f u l l y  and  normal Long-Evans r a t s .  marked  with  with  In sulfate  heterozygous  i n t h e s e a n i m a l s . The  As  observed  o f the  a  (10-20 min)  level..  of  shown r e s p e c t i v e l y i n f i g . 5 and  produced  excretion  The  responses  the  normal  as not an  urine This and  34a  FIGURE 5.  An  example  effects  of  of  the  morphine  r e n a l and c a r d i o v a s c u l a r sulfate  h e t e r o z y g o u s D.I. ( B r a t t l e b o r o ) the  same a s t h a t  test  dose  for  o f AVP  comparison.  in fig*  (1mg/Kg)  on  a  r a t . Legend i s  4. The r e s p o n s e  ( a t 50 ug) was a l s o  to a  included  1 0 min period  35a  FIGURE 6.  An  example  effects  of  the  o f morphine  r e n a l and c a r d i o v a s c u l a r  sulfate  (1mg/Kg)  and  AVP  (10ug) on a homozygous D . I . ( B r a t t l e b o r o ) r a t . Legend i s t h e same a s t h a t  i n f i g . 4.  36  36a  TABLE I.  Changes  i n mean a r t e r i a l pressure, u r i n e flow  r a t e and u r i n e o s m o l a l i t y heterozygous D.I.  D.I. (HE-Dl)  (HO-DI) r a t s a f t e r  morphine mean ± SEM animals.  i n Long-Evans  sulfate. and *  significantly  The  each Values  different  to the LE group.  a  and 1  group in  homozygous  mg/Kg  values  (LE),  dose  represent the  comprises the  (p<0.05)  of  HO-DI as  of 6 are  compared  37  GROUP  MEAN ARTERIAL PRESSURE (mmHg)  URINE FLOW RATE (ul/min)  URINE  OSMOLALITY  (mOsm/Kg)  ^Reduction  %Reduct i o n  Xlncrease  8.4 ± 1.2  51.4 ± 9. 1  54. 1 + 20.7  HE-DI  11.3 ± 1. 5  45.9 ± 9.9  64. 8 ± 18.5  HO-DI  16.7 ± 1. 0  LE  25. 1 ± 7.7  9.0 ±  8*3  38  When b l o o d an  interesting  reports  given  arterial  pressure  phenomenon  by  Gomes  blood  Long-Evans g r o u p , t h i s (n=6)  reduction  greater as  much  as  decrease (11.3  ±  16%  1.5%,  different  the  was  of the  rate  decreased  beats/min changes  the  from  a  (n=6) were  to  The accompanied in  both  the  increase  i n urine  rats  were  a  a test  fig.  6.  the  and  development  was  g r o u p s gave  not  rats  significantly  i n some e x p e r i m e n t s after  level  of  heart  445  (n=6) .  normal  and  morphine  group, the  beats/min  the  D.I.  rats.  i n the  rate  increase  Long-Evans  small  osmolality  capable  response t o 5  8%  The  observed  homozygous D.I.  only  of  in  about  homozygous D . I . . g r o u p .  normal  ± 18  normal  +  7  Similar  Long-Evans  and  groups.  normal  produced  the  pressure  pre-injection  a slight  D.I. . g r o u p s . The  In  homozygous D.I.  320  reduction by  in  by  monitored  observed  h e t e r o z y g o u s D.I.  decrease  reduced  however,  In  the  heterozygous  consistently  administration.  to  average of  arterial  the  H e a r t r a t e was bradycardia  a  observed.  i n the  in  that  Contrary  I) . B o t h B r a t t l e b o r o  (n=6)  n=6) ,  from  observed*  amounted t o an  with  observed  simultaneously,  al..(25,26), was  (Table  reductions,  measured  was  et  pressure  was  of  dose o f  and  of u r i n e i n the and  urine  the  g r o u p , on  was  osmolality  heterozygous the  relatively  (Table  excretion  other  hand,  insignificant  I). All  three  groups  increasing urine  osmolality  in  synthetic  as  in  Thus, a n t i d i u r e s i s can of r e n a l i n s e n s i t i v i t y  AVP, not to  be  shown  a t t r i b u t e d to  AVP.  39  II.  C h r o n i c E f f e c t s Of Morphine Development o f p h y s i c a l  has  been  known  fig..7,  rats  weight  as  to  was s i g n i f i c a n t l y t-test,  by  monitored of these  animals Body  implanted  daily  with  different,  as  noticeable  series,  gain  controls.  This  by  Student's  with  gain  was  morphine p e l l e t s  with  during  placebo  the  decrease  intake,  also as  pellets  treatment in  water  of f l u i d  balance  attenuated  i n rats  compared ( f i g - 8).  animals  Daily  animals  period. intake  to  water  was  There  highly was  immediately  however,  a  after  w h i c h p r e s u m a b l y i s due t o  b e h a v i o r a l d i s r u p t i o n by morphine*  Daily  r e t u r n e d t o l e v e l s comparable t o  o f p l a c e b o - p e l l e t implanted  of t r e a t m e n t .  were n o t  was n o t known. weight  the n o n - s p e c i f i c  that  not  determined  thus the s t a t e  morphine i m p l a n t a t i o n ( f i g . 8),  water  did  injected  intake o f the morphine-pellet implanted variable  morphine  u s e . As shown i n  morphine  as the saline  on  day 7. Water i n t a k e and u r i n e o u t p u t  in this  implanted  occur with repeated  injected rapidly  dependence  Thus, t h e animals  tolerance to the sedative e f f e c t  g r o u p s on t h e s e c o n d appeared  t o have  of. t h e d r u g .  day  developed  39a  FIGURE 7.  Changes  i n body weight  with s a l i n e morphine  ( A , n=8) sulfate  *  Values  or i n c r e a s i n g (A,  represent means + SEM rats.  of r a t s i n j e c t e d  of  n=14). the  dosage The  two  are s i g n i f i c a n t l y  (p<0.05) as determined by Student's  daily of  values  groups  of  different t-test.  40a  FIGURE 8.  Changes i n body weight,  water intake and  output of r a t s implanted and  morphine  ( ~ ,) a  m  on  intake and g  day  placebo  placebo  or  0 and day 3. Both d a i l y water  urine output were c o r r e c t e d to  body weight.  *  Values  was  morphine  Withdrawal  was  precipitated  the e x c i s i o n of the implanted p e l l e t s 5.  (•-•)  p e l l e t s . Each animal  implanted with e i t h e r a pellet  with  urine  are  (p<0.05) as determined  significantly by Student's  on  100 by day  different t-test.  42  As reduced  on  Changes  with  the  in  related  water  first  day  intake,  exception..  the  treatment  Urine excretion  was  intake  account day  was  f o r the  5. A l s o ,  single  morphine,  Excretion few  rats  after  to c h a r a c t e r i z e Sephadex G-75 believe  of  hemoglobin  morphine p e l l e t s  such  and  physical rats in  weight  reduction  was  i n body  injection.. these  daily  This  animals  effect  appeared  on  of  to  a  promote  in  through  i s reason,  i s due  one  observed  pigmentation  be of  to a  however,  combination  discussed later. the  physiological  quantitative  (103). When morphine  was  assessment withheld  of from  with morphine, the r e s u l t i n g r e d u c t i o n small  weight  ( f i g . 9) . A p p r o x i m a t e l y was  very  rats,  however,  implanted  pellets  resulted  As  observed  Attempts  will  i n the  implanted  weight.  as  loss i s  implies is  may  implantation.  the  pigmentation  used  dependence  injected  body  of  myoglobin,  often  daily  chronically.  the n a t u r e  that  one  T h i s change  i n body w e i g h t  drug  only  5, w h i l e  reduced.  the  closely  increased in  o f a dark brown u r i n e was  Body w e i g h t parameters  on day  were u n s u c c e s s f u l . T h e r e  to  with  t o the a n t i d i u r e t i c  u r i n e f o r m a t i o n when g i v e n  a  group  sudden d e c r e a s e  of  were  significantly  significantly  i n contrast  dose  period  was  implantation.  urine excretion  the morphine-pellet implanted water  urine output  of morphine-pellet  water i n t a k e and  throughout  daily  observed  that  24 h r a f t e r  the degree  light. the  In  the  surgical  i n a dramatic  shown i n f i g . 10,  the  355  (n=8)  the  last  o f dependence o f morphine-pellet removal decrease  body w e i g h t  of in  the body  decreased  by  43  as much as  10%  significant  24  changes  placebo-pellet  water  w i t h d r a w a l day  second  day.  withdrawal  period.  The  average rats  of  II  content (45.5 both  in  ±3.7 lower  (50.4 ± 8.4 significant.  state  b a l a n c e and  AVP  with  may  ng  ng)  for  ± 32  for  the  withdrawn  than ng) . T h i s  that  stores  injection.  of  The  of  the  rats  difference,  was  ± 55  of not  saline-injected  to influence (449  of  days  ng) . . A 24 h r  d i d not appear  hypothalamus and  can  AVP  14  that  neurohypophysis  the  intake  i n the neurohypophysis  from  v s . 401  the  polyuria  account  sulfate  stored  morphine  different  the  of  d e c r e a s e i n water  of morphine  of  (423 ± 60  in  temporary  throughout  shows the t h e n e u r o h y p o p h y s e a l  14 days  amount  slightly  marked  S t o r e s Of  the drug a l s o  AVP  quite  Neurohypophyseal  significantly  from  the  the  weight.  injected  control  in  b u t r e t u r n e d t o c o n t r o l l e v e l s by  This  depressed  d e c r e a s e i n body  after  observed  the  was  was  by t h e t r a n s i e n t  Table AVP  were  on  to a negative f l u i d  substantial  of  intake  Polyuria  accompanied lead  i n body w e i g h t  o f the p e l l e t s . No  implanted animals.  Daily first  hr a f t e r t h e e x c i s i o n  withdrawal the  ng) .  levels  The  AVP  morphine-injected  (34.4  ±5.2  saline-injected however,  was  ng)  were  control also  not  43a  FIGURE 9 .  Changes i n body w e i g h t  during  withdrawal  the  series.  The  were  multiple injected  morphine withdrawal  injection with  sulfate of the  an  for drug.,  increasing IU  days  rats  (n=7)  dose  prior  in  of  to the  44  Hours  After  the L a s t  Injection  44a  FIGURE  10.  Changes i n body w e i g h t the were  pellet  implanted  with  either  (o) f o r f i v e  significantly  determined  withdrawal  implantation series.  morphine p e l l e t s are  during  placebo days.  different  by S t u d e n t ' s  The r a t s  t-test.  *  in  (n=6) (•) o r Values  (p<0.05)  as  45  Hours  After  Pellet  Excision  45a  TABLE I I .  Hypothalamic AVP  in  control  the  and  multiple  group  was  morphine-treated for  neurohypophyseal  injected group  14 d a y s . M o r p h i n e  morphine-withdrawn  injection  was  group  14 day t r e a t m e n t p e r i o d . of  8 rats.  No  significant  s t o r e s of  series.  The  with s a l i n e . a n d  w i t h morphine withheld  sulfate  from  the  f o r 24 h r a f t e r Each group difference  between t h e t h r e e t r e a t m e n t s .  the  the  consisted was  found  HYPOTHALAMUS GROUP  (ng AVP)  NEUROHYPOPHYSIS (ng AVP)  CONTROL  50.44 ± 8.43  401 ± 32  MORPHINE  45. 50 ± 3.67  423 ± 60  WITHDRAWN  34. 43 ± 5.15  449 ± 55  47  Neurohypophyseal pellet  implantation  treatment  from  744  ± 28 ng  not  cause  AVP  in  AVP  a  control  (n=6). any  three  fourth  of  day. The amount  treatment  in  the  gland  o f RVP  implanted  explain  m o r p h i n e on t h e f o u r t e e n t h AVP  stores  (n=6) t o drug  did  during  the lack  of  the  replenished stored  on  by the  different  control.  i s maintained  the neurohypophysis of rats given  later.  depleted  the continuous a p p l i c a t i o n day, i t may  was  the neurohypophyseal  was n o t s i g n i f i c a n t l y  in  the  of the  particularly  with the  were b e i n g  fifth  which  was  that  the  of  depletion  of the neurohypophyseal  were  of the placebo-pellet  stored with  which  days o f treatment,  and f i f t h  day  level  Morphine  treatment  i t appeared  first  AVP  i n f i g . 11.  o f 1024 ± 6 6 ng  further depletion  o f t h e hormone,  from t h a t  morphine  This  value  Continued  s t o r e s . In f a c t ,  fifth  the  significant  stores.  stores  the  a  of  on day 3 , i n w h i c h t h e amount o f AVP s t o r e d  noticeable reduced  stores  s e r i e s a r e shown  resulted  neurohypophyseal  AVP  If  the  near t h e n o r m a l morphine  after  of depletion  o f AVP  daily  day. P o s s i b l e  were r e p l e n i s h e d  i*p. injection mechanisms  will  be  by  discussed  47a  FIGURE  11.. N e u r o h y p o p h y s e a l implanted morphine five  with pellets  (5)  withdraw (W).  treatment Values  as are  as determined  for  t h e drug  pellets  group and  the  AVP  (1),  rats 5  in  pellets  Stippled  AVP i n  The c o n t r o l  placebo  f o r one  pellets from  of  placebo  days..  neurohypophyseal morphine  stores  three bars  rats  (C) (3)  and or  represent  implanted  with  d a y s and a l l o w e d t o  for 3  days  thereafter  (Wc) was i m p l a n t e d subjected  withdrawal  to  with  t h e same  group  (W). . *  significantly different  (p<0.05)  by S t u d e n t ' s  t-test.  48  1200 W  sz  a o a  800+  3  <D C  \ CL  > <  400+  CO c  C  1  Morphine  3  5  Treatment  Wc  W  49  When morphine w i t h d r a w a l fifth  day  pellets, stores  by a  was  marked observed  pre-withdrawal (n=6) the  the  implanted  significant (902 ± 37 ng, implanted  n=6)  therefore,  can  the e x c i s i o n  ng  (n=6)  did  AVP  withdrawal again  the  as  compared  of  the  of  As t h e  to  from ± 36  result  the  in  AVP  a ng  any  stores  placebo-pellet  neurohypophyseal  develops  implantation a significant  AVP  pre-withdrawal hr a f t e r was  AVP  dependent  no  changes  the e x c i s i o n significant  ± 5 ng  of the as  stores  were  animals  stores.  observed  AVP  stores  v a l u e o f 53  (p<0.03) .  physically  in  was  pellet however, The  from  the  t o 33 ± 5 ng  (n=6)  implanted  determined  the  seen.  reduced  (n=6)  in  the  ( f i g - 12). D u r i n g w i t h d r a w a l , in  to  l e v e l s . . Abrupt  were  reduction  hypothalamic  tolerance  pre-treatment  morphine t r e a t m e n t ,  series  stages of  neurohypophyseal  o f the  stores  store,  the  the drug from  AVP  AVP  during the early  animal  to  led to a depletion  hypothalamic  t-test  638  neurohypophyseal  observed  returned  During  change  to  not  p h y s i c a l d e p e n d e n c e on t h e d r u g ,  stores of  decreased  of the p e l l e t s . . R e m o v a l of  in  o n l y be  morphine t r e a t m e n t .  72  ± 70  implanted  controls* Depletion  and  i n t h e n e u r o h y p o p h y s e a l fcVP  11)..The l e v e l s  the  the  reduction (fig  of  on  removal  placebo-pellets  change  precipitated  surgical  v a l u e o f 1012  72 h r a f t e r  was  pellets. by  the  This  Student's  49a  FIGURE 12..  Hypothalamic placebo and  AVP  pellets  5).  stores (C)  Stippled  s t o r e s o f AVP  implanted  o r morphine p e l l e t s bars represent  i n the  withdrawal  its  placebo implanted  are  significantly  determined  in rats  control  different  by S t u d e n t ' s  t-test.  with  (1,  3  hypothalamic  group (He),.*  (W)  and  Values  (p<0. 05)  as  50  3  E  80  o a  40 +  O) c  J u l  C  1  Morphine  3  5  W  Treatment  c  w  51  The c o n t r o l morphine-pellet than t h a t  neurohypophyseal  implanted s e r i e s  observed  AVP  ( f i g . 11)  i n the i . p . . i n j e c t e d  extraction  AVP.  I t may  animals were  used  Wistar  Young  (266.0 ± 2.5 g,  morphine-pellet  implantation  may  role  also play a  stores the  of AVP.  month  series  in  performed  Unlike  altering  Seasonal  the  male  in  the  variations  neurohypophyseal  series  the  used  the  g, n = 8)  whereas a d u l t  were  series.  was p e r f o r m e d i n  pellet  implantation  Stores of Oxytocin  neurohypophyseal  morphine-pellet  of  i n May.  B.,Neurohypophyseal  The  n=6)  whereas  age  (193.5 ± 2.5  series,  The i . p . i n j e c t i o n  o f December,  was  (Table I I ) .  by v a r i a t i o n s i n  i n the  male W i s t a r r a t s  i n the i . p . i n j e c t i o n  rats  the  p r o c e d u r e n o r by v a r i a t i o n s i n t h e RIA o f  be due t o t h e d i f f e r e n c e s  used.  in  was much h i g h e r  series  T h i s d i s c r e p a n c y c a n n e i t h e r be e x p l a i n e d the  stores  oxytocin  implanted s e r i e s  the neurohypophyseal  AVP  are  stores  shown  stores,  in  oxytocin  of  the  F i g . 13. stores i n  t h e . r a t s i m p l a n t e d w i t h morphine p e l l e t s  were u n a l t e r e d i n  the  However,  first  three  days  of  treatment.  increase  i n the neurohypophyseal  control  v a l u e o f 1051  was  observed  significant  on as  the  fifth  determined  T h i s change a l s o  coincided  depleted  AVP  initiated  on t h e f i f t h  significant  ± 52 ng  stores.  reduction  by  oxytocin  stores  in  from  t o 1353 ± 50 ng  day.  This  Student's t - t e s t  the  treatment  a  (n=6)  difference  of  the  the drug  resulted  neurohypophyseal  was  (p<0.01).  with the replenishment  of  slight  (n=6)  The a b r u p t w i t h d r a w a l f r o m day  a  in  a  oxytocin  52  stores. value  The o x y t o c i n of  after  stores  1 3 2 8 ± 54 ng  Serum  Osmolality  No s i g n i f i c a n t serum  sodium  placebo p e l l e t slight  were  a  pre-withdrawal  t o 9 0 1 ± 38 ng (n=6) 7 2 h r  group  in  c h a n g e s i n serum between  osmolality  the  morphine  (Table  V).  There  osmolality  in  animals  serum  the  difference,  control  however,  by S t u d e n t ' s  (296.8 was  t-test.  and and  was  a  morphine  ( 3 0 3 . 5 ± 2.6 mOsm/kg, n=6) a s compared  placebo implanted  determined  and Sodium  detected  implanted  increase  withdrawn  This  (n=6)  from  the e x c i s i o n o f t h e p e l l e t s . C.  its  fell  to  ± 2.4 mOsm/kg, n=6) .  not  significant  as  52a  FIGURE  13. _ N e u r o h y p o p h y s e a l implanted pellets the  with placebo  of  oxytocin i n rats  pellets  (1,3 and 5 ) . . S t i p p l e d  withdrawal  implanted  group  control  significantly by  stores  Student's  (Wc).  different t-test.  (W)  (C) o r morphine bars  represent  and  i t s  *  Values  (p<0.05) a s  placebo are  determined  53  1600  X  t  1200  a o a. >« 2 3  8004-  c  \ c  o o  2 >»  400-f  X  o cn c  5  Wc  W  53a  TABLE I I I . „  Serum  osmolality  pellet  and  implantation  consisted  of  classified  as  6  sodium  of r a t s  series. rats.  The  i n the  Each  group  groups  follows:  C  rats  implanted  with placebo  1  rats  implanted  w i t h morphine p e l l e t f o r 1 day;  3  rats  implanted  w i t h morphine p e l l e t s f o r 3  days;  5  rats  implanted  with morphine p e l l e t s f o r 5  days;  Wc  rats  implanted  W  with  p e l l e t s f o r 5 days;  placebo  pellets  pellets  were e x c i s e d on t h e f i f t h  allowed  t o r e c o v e r f o r 3 days;  rats  implanted  with  morphine  were e x c i s e d on t h e f i f t h  allowed  t o r e c o v e r f o r 3 days; was f o u n d  for  day and t h e  pellets  pellets  No s i g n i f i c a n t d i f f e r e n c e  were  5  days; animals  f o r 5 days;  day and t h e  animals  amongst a l l g r o u p s .  54  SERUM OSMOLALITY GROUP  (mOsm/Kg)  SERUM  SODIUM  (mEq/L)  C  293.7 ± 2.0  144.8 ± 0.9  1  295. 2 ± 3. 4  142.7 ± 1.  3  297.0 ± 1 . 8  146.0 ± 2. 8  5  292.7 ± 3.2  143.8 ± 1.0  Wc  29 6.8 ± 2.4  14 5.8  W  303.5 ± 2.6  147.7 ± 1 . 1  1  ± 1.7  55  P i Opiate  Receptor  The homogenate morphine in  Since  was  a change  binding (Kd) the  a  was  for  increased  Scatchard  (q)  (Table  VI) .  binding the  was  to  The  suggest the  seven  resulted  coupled  oxytocin,  on  No  i n the  t o the  specific  a  3  and  22.4  i n the  H-naloxone constant 5.3  nM  for  the of  3  binding  number o f  binding group receptor  affinity  ligand,  hormones, were a l s o  of rats  such  washing  H-naloxone  assay  the  relatively  as  of  morphine-injected  the  was  in  morphine-treated  neurohypophyseal  receptor  and  decrease i n the  from  nM)  morphine-treated  i n the  the rats  binding. AVP  20  pM  to 2  nM.  and  tested.  n o n - s p e c i f i c i n t e r f e r e n c e were d e t e c t e d of  by  binding  number o f r e c e p t o r  competitive  enhancement  the  concentrations  3.2  b r a i n homogenate. R e p e a t e d  the  or  explained  affinity  A small  3  preparation  of  be  of  binding*  s i t e s or  (about  (Table V I ) .  presence of  Effects  can  t o be  f o r H-naloxone i n the  i n an  brain  hr r e s u l t e d  H-naloxone  The  fold  l a c k o f change  morphine, i n the receptor  f o r 24  a n a l y s i s o f the  found  a l s o observed  receptor  3  whole  i.p. injection  binding  (115)  increase  sites  the  to  withdrawal groups, r e s p e c t i v e l y . . T h i s  four  was  of  ( f i g . .15).  H-naloxone  insignificant  chronic  number o f b i n d i n g  morphine t r e a t e d g r o u p  sites  with  in receptor  i n the  c o n t r o l and  H-naloxone  Morphine a b s t i n e n c e  performed 3  3  recovery  decrease  affinity,  of  depressed  complete  the  either  binding  ( f i g . 14).  near  Binding  at  55a  FIGURE 14,,  Stereospecific brain  homogenates  with s a l i n e days. to  The  of H-naloxone  third  from  the drug  group  rats  (A)  injected  hr. .  rats  daily  (A) f o r 14  represents  homogenates f r o m f o r 24  t o whole  3  (©) o r m o r p h i n e s u l f a t e  whole b r a i n  from  binding  binding withdrawn  56  Concentration  of  3  H-Naloxone  (ViM)  56a  FIGURE 15.,  Double  reciprocal  stereospecific brain  H-naloxone  homogenates  injection in  3  series.  f i g . 14.  (Scatchard)  from Legend  binding rats  plot to  i n the  i s t h e same  of whole  multiple as  that  57  1 / H - Naloxone Concentration 3  (nM"')  57a  TABLE IV.  Number affinity analysis  of  binding (Kd)  as  sites  determined  of H-naloxone 3  homogenates from  (q)  binding  and  binding  from  Scatchard  t o whole  r a t s i n j e c t e d with  brain  morphine.  BINDING GROUP  SITES  (pmol)  BINDING  AFFINITY  (nM)  CONTROL  0. 370  5. 32  MORPHINE  0.588  22.37  WITHDRAWN  0.213  3.21  59  DISCUSSION The  present  study  morphine  effects  on  effects  of  single  a  experiments) of the  and  drug  AVP  the  dealt  with  two  f u n c t i o n - the dose  immediate  sytemic  administration  (acute  These  two  be d e a l t  w i t h s e p a r a t e l y i n the d i s c u s s i o n *  I. Acute  Effects  antidiuretic the  drug  of action  animal.  establish  a  the of  approaches  a drug  the  constant  I f the a c t i o n  kidneys,  then  of  state of the  of  must  The  i n the  study  r e p o r t e d by  antidiuretic the  antidiuretic  ADH  action  The  counteract  being the  is  the  the  AVP  drug  effect  the  such  as  not  on  the  feature  of  in  In  be  detected.  ethanol view  antidiuresis  using  antidiuresis  question  of both  (116) .  (132)  this  may in  release.  t h a t morphine-induced  at  T h i s i s the  problem  AVP  water  bioassay  Fujimoto  utilized  major  to  endogenous r e l e a s e  (ADH)  and  r e l e a s e of  that  on  the  of  water  and  directed  preparations i s that  suppressive  osmolality  possibility  One  animal  through  reason  plasma  morphine  a  i t i s important  be c o n t r o l l e d .  Inturrisi  bioassay*  ethanol-hydrated mediated  of  in  u r i n e flow r a t e ,  hormone  the  ability  hydration  drug  factors affecting AVP,  flow  study,  b a s i s f o r using ethanol to suppress AVP  will  studying  i s t o measure t h e  In t h i s type  endogenous r e l e a s e o f  in  r a t e of u r i n a r y  diuresis.  of  aspects  o f Morphine Ad m i n i s t r a t i o n  t o reduce  hydrated  of  e f f e c t s of continuous a d m i n i s t r a t i o n  (chronic experiments).  One  aspects  has  to  and  low  of  the  i s mediated  60  by  the  release  infusion added  of  AVP,  s o l u t i o n i n these  physiological  fully  conscious. by  flow  r a t e and low u r i n e  that  substantial (Table  This  investigators (17-21). reduction terms  on  The  rats  agreed the  same  the  morphine, both may  at  well  dose  1  flow  release urinary  also  and  mg/kg,  action  produced  D . I . and  were  heterozygous  a rat  by s e v e r a l of  a  pressure  identical.  induced  studies  morphine  significant  (Table  cardiovascular  heterozygous  clearly  i n the hydrated  with  arterial  renal  of  experiments  antidiuretic  be c o n s i d e r e d  those  an  t h a t t h e a n i m a l s were  the acute  o f t h e homozygous D.I. r a t from  has  osmolality.  i n urinary  i n t h e mean  of  also  o f endogenous AVP  morphine  reduction  I) .  This  from t h e  t h e maintenance of a s t a b l e high  r e s u l t s from  established  in  The i n h i b i t i o n  evident  was e x c l u d e d  experiments.  advantage  was  The  ethanol  I ) . . In  responses  normal  to  Long-Evans  However, t h e r e s p o n s e s  statistically  D.I. and  normal  different Long-Evans  rats. The an  increase  reduction  i n urine  of the kidney  in  administration water  net  water  osmolality.  a l l three  was  also  reversed  water  to  reabsorption.  determine the u n d e r l y i n g free  was a c c o m p a n i e d by  The c o n c e n t r a t i n g  groups  improved  ability  after  of morphine. A s u b s t a n t i a l d e c r e a s e . i n  clearance  water c l e a r a n c e  i n u r i n a r y flow  clearance  observed.  I n some c a s e s ,  negative  values,  It  is  difficult  mechanism f o r i s  affected  by  this a  the free free  suggesting  to accurately decrease  as  multitude  of  61  physiological suggested D.I.  parameters.  the  influenced in  involvement  and n o r m a l The  release  electrolyte been  release  of  of  AVP  in  AVP  has  been  also  volume,  affected  balance,  widely  accepted to  prove t h i s ,  AVP must be  that  the  cardiovascular  secretion  o f AVP  the  plasma mean  levels  changes  (30). . I t s  (117).  i t has  morphinerinduced  direct  stimulation  system  (17-21). In order to  effect be  In  of  view  o f morphine a  as 5% c o u l d  direct  of  the  the  (25-27), t h e  result  of  administration D.I. r a t s ,  n o t be r u l e d  If  that  blood  the  significantly  pressure  i n c r e a s e the  ( 3 0 ) . As much a s 8 and 11% r e d u c t i o n (Table in  the  the  responsible  morphine,  one  would  animals incapable  was  normal  observed  in  after  Long-Evans  and  hypotension  mechanism by which  the  o f AVP.  endogenous  mechanism  I)  r e s p e c t i v e l y . ,Hence,  out as a p o s s i b l e  drug e f f e c t s t h e r e l e a s e  from  be  hormones, w a t e r and  controlled.  not  pressure  heterozygous can  may  small  arterial  morphine  to  o f t h e h y p o t h a l a m o - n e u r o h y p o p h y s e a l s y s t e m by  as AVP  pressure  the  drug. Recent evidence i n d i c a t e s  changes  known  a l l f a c t o r s a f f e c t i n g the r e l e a s e  adequately  powerful  stimulation  and  by v a r i o u s  hypothalamo-neurohypophyseal  of  the heterozygous  and e m o t i o n a l s t r e s s  a n t i d i u r e s i s i s due  conclusively  changes  a number o f f a c t o r s . These i n c l u d e  osmolality, i s  these  rats.  by  blood  Nevertheless,  release  f o r the not e x p e c t  o f AVP i s t h e s o l e  antidiuretic  action  of  an a n t i d i u r e t i c r e s p o n s e  of s y n t h e s i z i n g  AVP.  For  example,  62  this  was  shown t o be  antidiuresis causing rats  in  the  I).  involved  Hence,  The  and  rats  decreased  was  homozygous again  can  the  any  other  i n the  n o r m a l and in  of  rats,  to  the  to  urine  the  the be  normal due  reabsorb  of  to  water.  rats,  osmolality  lack  be  leading to a  antidiuretic  the  must  homozygous  h e t e r o z y g o u s D.I.  during  attributed  the  than t h a t  kidneys  rats  morphine*  T h i s d i f f e r e n c e may  the  D.I.  AVP  by  in  homozygous D.I.  of  rat  less  effective  homozygous than  in  insipidus  hand, was  other  in  ineffective  diabetes  observed  rats.  change  D.I,, be  r a t s was  i n the  significantly  AVP  to  hardly  the  antidiuresis  ability  Compared  at doses e f f e c t i v e  i n d u c t i o n of a n t i d i u r e s i s  was  lack of  on  mechanisms  h e t e r o z y g o u s D.I.  the  chlorpropamide-induced  hypothalamic  u r i n a r y flow  i n the  for  normal  Morphine s u l f a t e ,  (Table  D.I.  in  hereditary  reducing  case  Chlorpropamide,  antidiuresis  with  (118).  (118).  the  there  of  the  period.  This  AVP  in  these  animals. Antidiuresis For by  can  brought  on  by  s e v e r a l means.,  example, a l t e r a t i o n s i n r e n a l f u n c t i o n can various  filtrate can  vasoactive  leal  induced  agents.  reabsorption, to  Antidiuresis by  and  a  marked  c h a n g e s i n the reabsorption  agents  such  as  (122).  filtrate  have  be  induced  changes  formed, or  in  urinary  been  shown  in  both, flow.. to  be  physical forces responsible for (119)  angiotensin Changes  resulting  reduction  antinatriuresis  fluid  AVP  The  amount o f  tubular  and  be  in  as  w e l l as  by  vasoactive  (120,121), e p i n e p h r i n e 3FR,  caused  by  (121),  either  an  63  alteration  in  v a s c u l a r tone in  urinary  of  AVP,  (123)  can a l s o  the  pressure highly  antidiuresis view  observed  mechanisms,  similar  hypotension  been  nervous shown  periods  of  increase  epinephrine  fraction a  to  are  to  renal  and  an  stimulus  for  the r e l e a s e  reduction i n  discharge  during (126).  levels  cause  increase  (127). I n a d d i t i o n , h y p o t e n s i o n  in  function  demonstrated  can  is  catecholamines renal  catecholamine  norepinephrine)  it  increase  f l o w , and  sympathetic  blood flow  arterial  hemorrhagic  An  alter  been  to  compensatory  in  circulating  i n r e n a l blood  circulating and  involved  have  used  i n mean  hormonal  dramatically  excretion  be  devoid  animals.  activated.  and  are  administration,  and  those  heightened  in  the t o t a l  neural  tone  (126, 1 27) .. R e d u c t i o n water  may  i n these  morphine  (124,125)  sympathetic  rats  o f t h e marked d e c r e a s e  that  renal  a substantial reduction  mechanisms  observed  after  probable  and  cause  f l o w . S i n c e t h e homozygous D.I.  In  salt  membrane p e r m e a b i l i t y o r  o n l y AVP-independent  explain  has  glomerular  (mainly  a decrease i n in  may  An  filtration  also  serve  as  of other vasoactive peptides  (120-122).„Activation o f the r e n i n - a n g i o t e n s i n system,  for  example, was  shown t o r e s u l t  RBF,  antidiuresis  and  likely to  that  antinatriuresis  antidiuresis  changes  in  the  hemodynamics b r o u g h t o t h e r than  i n a decrease  i n the  i n GFR  (128) . I t  is  homozygous D.I.  cardiovascular  on by n e u r a l and  system hormonal  and  therefore r a t i s due and  renal  mechanisms  AVP. Morphine  appeared  to  exert  a  more:  potent  64  h y p o t e n s i v e e f f e c t on to the  n o r m a l and  suggested the  the  lack  in  the  maintenance  the  mesenteric  resistance  intestinal  depletion  be  The  insipidus  greater  normal  assist  rat,  i n the  AVP  has  the  shown t o  vessels  as  well  to  of  as  to  abolish  to  volume appeared  influence i n the  of  AVP  diabetes  partially  hormone  a  vascular  vessels  AVP  be  dilatation  response  vasoconstrictor  restoration  these  been shown t o  cause  vasoconstrictor  e f f e c t of the  This  in  mesenteric  been shown t o be  the  I).  mechanisms  sensitivity  a n i m a l s has  vasoconstrictor  the  (Table  a d d i t i o n , r e n a l blood  under t h e  compared  have i n t e r f e r e d w i t h  vasoconstrictor  (130). In  normally t o (131).  may  of  was  r a t s as  rats  compensatory  ( 1 2 9 ) . Hypophysectomy  the  the  o f AVP  Under n o r m a l c o n d i t i o n s ,  involved tone  homozygous D.I.  h e t e r o z y g o u s D.I.  cardiovascular  animals*  of  that  the  due  to  (132). Hence, i n e f f e c t of  normal  AVP  may  systemic  blood  pressure. The its  duration  rate of  of  action  (133).  Uptake o f the  long  as  60  continuous  minutes  observed either  period.  only  mean t h a t  stimulus tolerance  threshold or  after  a  f o r AVP  for  drug or  the  tachyphylaxis  can single  the  20  to the  and  a  rapidly to  drug.  and hr as  i.v. injection  minutes.  has  4-5  detected  provide protracted  antidiuretic  cleared animal  of  drug should  the to  i s slow  order be  secretion  10  was  morphine  i n the  CNS  However,  lasted the  the  presence of  stimulus  antidiuretic  of  i s generally  d r u g by  (134,135)..Hence, the a  clearance  period  This  could  below  developed When a s e c o n d  the  rapid dose  65  of  morphine  dose,  the  was  administered  resulting  reduced. T h e r e f o r e , after  the i n i t i a l  30  min a f t e r  antidiuresis  the short  dose  observed  antidiuresis  i s likely  and  Fujimoto  experiments the  long  is  not  effect  known  i n the current  term  effects  at  study  o f morphine  hypothalamo-neurohypophyseal  on AVP r e l e a s e  effects  II • C h r o n i c  Effects  known t o d e p l e t e oxytocin  were d e s i g n e d  depletion of  These the  osmotic  the  to  t o examine on  Changes  shed  some  the  i n the light  on  Administration  stimuli  release  examine upon  with  or dehydration  the  The  i t  AVP,  adaptive  would  stimulatory  tachyphylaxis  can  effects be  levels  response  showed  of  on  the  demonstrated  the Eats  three  days  subsequently  the  fifth  day.  of t o l e r a n c e t o  drug.  after  of  progressive  stores  the development of  be  administration..  neurohypophyseal  c h a n g e s may r e f l e c t  AVP  of  pellets  t o t h e pre-treatment  both  administration of  chronic  morphine  h a s been  the acute  o f n e u r o h y p o p h y s e a l AVP i n t h e . f i r s t  treatment.  recovered  one  chronic  administration  system.„  o f Morphine  (136,137). Since  neurohypophysis implanted  The  t h e n e u r o h y p o p h y s e a l s t o r e s of  morphine c a u s e s interest  after  o f morphine on t h e r e l e a s e o f AVP.  Chronic  and  that  t h e development of  present.  n e u r o h y p o p h y s e a l s t o r e s o f AVP might the  observed  hypothesized  o r more d o s e s . The mechanism u n d e r l y i n g tachyphylaxis  period  much  was a l s o o b s e r v e d by  ( 1 7 ) . They  morphine h a s an i n h i b i t o r y  was  due t o t h e d e v e l o p m e n t o f  t a c h y p h y l a x i s * . Morphine t a c h y p h y l a x i s Inturrisi  the i n i t i a l  Although  a single  dose  66  injection  o f morphine,  reported  to  depletion  o f AVP  due  to  be  the  the  development  maximal  after  i n the f i r s t  direct  morphine-induced  stimulation  the  decreases,  thus a l l o w i n g  the  hormone.  and  In the  neurohypophyseal  the  that  at  AVP  synthesis  implantation morphine the  weight  loss  series  after  daily AVP  injected  3  day  the period  did  may  not  the  to  be due  rate  show  any  those  of  It i s quite  was  adaptive  change  stimulation. obtained  on  s e r i e s i s d i f f e r e n t as i s evident  by  during  encountered  on  pellet  t h e d e g r e e o f dependence  weight  hr  of  possible  i n j e c t i o n s e r i e s w i t h t h o s e of t h e  i n body  that  effects  t o compare t h e v a l u e s  First,  of  morphine,  t o the f a c t  stimulatory  t o an  of  progressively  t o overcome t h e  compared  difficult  series.  rats,  s i g n a l s t o the  i . p . . i n j e c t i o n s of  stores  be by  With t h e development  i n response to chronic  is  24  or  Presumably, this  time of s a c r i f i c e .  i n t h e s e two  changes  release  released  o f d i f f e r e n c e be due  the m u l t i p l e  the  AVP  biosynthesis  controls. This  the  the l a c k  It in  hormone  animals are t o l e r a n t t o  morphine  in  rate*  difference  saline-injected  (33)..Hence,  r e p l e n i s h the n e u r o h y p o p h y s e a l s t o r e s  r a t s given  significant  of  during  biosynthetic  t h e amount o f  release  is  o f t r e a t m e n t might  system.  released  tolerance,  of  tolerance  a l t e r a t i o n of the a f f e r e n t  hormone  exceeded  days  3 days  hypothalamo-neurohypophyseal amount o f  3  of  of the  drug other  withdrawal..A  i n the p e l l e t abstinence. hand, o n l y  10%  body  implantation The  morphine  exhibited  a  3%  67  decrease  in  withdrawal.  weight  Secondly,  different. given  body  daily  cleared  i n 4-5  period  of  hr, the animals  hand, morphine  was  rate  pellet  same  period  of  i n j e c t i o n s e r i e s , morphine  a t 0800 and  withdrawal  the  the  t h e mode o f d e l i v e r y o f t h e drug i s  In the m u l t i p l e  twice  in  over  1800  h r . S i n c e morphine i s  may  go  between  delivered  was  through  injections.  at  a  brief  On t h e o t h e r  reasonably  implantation  a  series.  continuous Thus,  animals a r e not as l i k e l y  t o have  periods  throughout  the  s e r i e s . T h i r d l y , the d u r a t i o n  exposure  t o t h e drug  v a r i e s between  rats  were  pellet  exposed  implantation  morphine Hence,  only  for the  comparable however,  series,  days  between  rats  two  whereas  two  series.  rats  stores  withdrawal of The  f o r 5 days i n the  i n the m u l t i p l e  the  the  the  morphine  neurohypophyseal  that  injected  14  to  encountered  these  were  given  injection series.  of  AVP  are  not  s e r i e s . . I t i s of i n t e r e s t ,  neurohypophyseal  (423 ± 60 ng, n=8)  AVP  was  the  much l o w e r  saline  than  inplanted  This  t o t h e d i f f e r e n c e s ' i n t h e age o f t h e  animals  used.  injection pellet  due  Young  s e r i e s , whereas  implantation  have  significantly  than  young  caused  by  contributed injection  rats  were  adult  used rats  s e r i e s . Adult  more AVP  rats  (137).  the  daily  (1024 ± 66 ng,  that  of t h e p l a c e b o - p e l l e t i s partially  rats  of  in were  the used  i n the  in  the  neurohypophysis  I t i s also p o s s i b l e that  to the depletion  multiple  r a t s have been shown t o  stored  handling  n=6) .  and  o f AVP  the  stress  i n j e c t i o n s may  stores  i n the  have  multiple  s e r i e s . S t r e s s f u l and p a i n f u l s t i m u l i have  long  68  been in  known  to stimulate  the p e l l e t  stressful  implantation  stimuli  of the chronic  of  implanted  Morphine  not  of  a  drug  likely  the  in  (138).  cause  biosynthesis  intake  dehydration  (139),  stores  AVP.  the  the  presence  (139).  attributed  of  the  of  a  slight  T h i s , however, d o e s n o t  of a d i r e c t  effect  release,  s u c h as t h a t  can a l s o deplete This  the  may p a r t i a l l y  o f morphine on  i n r a t s implanted after  the  to control  morphine  first  day  levels  occurring  during  neurohypophyseal  e x p l a i n the d e p l e t i o n  with  implantation. pellets  Water  decreased  ( F i g . 1 0 ) . As water by  the  second  day,  can be r u l e d o u t as a f a c t o r f o r t h e d e p l e t i o n  neurohypophyseal  of treatment. Since acute  been  depletion  intake  of  the s y n t h e s i s  Ho wever, s t a r v a t i o n p e r se i s  day o f p e l l e t  dehydration  of  r e s u l t i n g from t h e s e d a t i v e  observed a f t e r the f i r s t  recovered  rate  o r t r a n s p o r t o f AVP.  Increased  intake  the  attributed to a  increased  has  in  AVP s t o r e s . I t has been shown t o have no  water  significantly  to  reflection  AVP s t o r e s be  an  this  for  out the p o s s i b i l i t y  of  a better  can  or  intake  on AVP s t o r e s d e s p i t e  decrease rule  rate  i n food  the  rats  Furthermore,  neurohypophyseal effect  subjected  has been known t o a f f e c t  (138).  to the decrease effect  not  of neurohypophyseal  biosynthetic  proteins  s e r i e s were  (117).,Animals  e f f e c t s o f the drug.  morphine-pellet  release*  o f AVP  and, c o n s e q u e n t l y ,  Depletion  decreased  the r e l e a s e  AVP s t o r e s  observed  on t h e t h i r d  AVP was shown t o be r e l e a s e d  administration  o f morphine  with  day the  (17-21) , t h e c o n t i n u o u s  69  application hormone.  A  would tend syndrome  two  (Table  hormone may  no  V).  not  raises  released  depletion  of  on  the  RVP  level  development of  of  the  i n t o the  AVP  i s due  to  symptoms o f  SIADH  hyponatremia  rats treated  possibility systemic an  a  antidiuretic  dilutional  performed  of  with  c h a n g e s i n e i t h e r serum o s m o l a l i t y This  be  and  stores  circulating  most p r o m i n e n t  Serum d e t e r m i n a t i o n s  the  the  secretion  serum o s m o l a l i t y  morphine r e v e a l e d  if  elevated  inappropriate  (SIADH). The  sodium  deplete  t o promote water r e t e n t i o n and  reduced  (140).  drug should  chronically  of  hormone are  of the  that  or the  circulation  increased  rate  of  release* In c o n t r a s t neurohypophysis  released causing  there  shown  to  (140).  This  also  inhibit may  both  AVP  and  the  the  the  for  day  dependent oxytocin  morphine-pellet  closely  anatomically  these  other  hormones  (141).  its  Thus,  analogues  lack  the  be  stimuli release  have  oxytocin of  can  been  release  depletion  morphine t r e a t m e n t . . I t  elevation  withdrawal  the  are  the  of  in  neurons  suckling-induced  slight  fifth  by  necessarily affect  a f t e r 3 d a y s of  Abrupt physically  not  account  stores  on  may  A l s o , m o r p h i n e and  explain  observed  o f each  stores  neurosecretory  i s evidence that  release  of o x y t o c i n *  the  hormones  independently AVP  oxytocin  two  oxytocin  unaltered  Although  these  associated,  AVP,  were  implantation. producing  to  in  oxytocin  of may  stores  treatment. of  morphine  from  the  animals r e s u l t e d i n the  depletion  of  s t o r e s . Changes i n AVP  storage  may  70  partially  be  electrolyte water the  due  to  the  (40)  body's  during withdrawal  stores  of  salt  however, were n o t o b s e r v e d the  on t h e f i r s t  transient  day  of  withdrawal,  group  on t h e  was,  however, a n o t i c e a b l e  number not  of  it  may  and  3 days  third  the  as  decrease  in  These study  group  change  animal's  salt  ( f i g . 10) .  significant  changes implanted  withdrawal.  output  Because of the  small  by  this  increase  Student's excretion  could  b a l a n c e . In  generalized  CNS  activity  t o p o t e n t i a t e the  and  subsequent  of  depletion  various withdrawal  shaking,  and  hyperactivity It  teeth  administration  signs,  clear  possibility peptides  that  may  in  release presence  as  wet  jumping, doubt  that  both  acute  related  endorphin  system.,  and  and  dog  to the  chronic  the f u n c t i o n i n g The  i n the neurohypophysis  regulate  increase  hormones. The  i s no  of morphine a f f e c t s  receptors  weight  CNS.  hypothalmo-neurohypophyseal opiate  such  chattering,  of the is  o f the two  have  addition,  o b s e r v e d d u r i n g w i t h d r a w a l . The likely  was  t-test.  f o r t h e d r a m a t i c d e c r e a s e i n body  i s equally  There  urine  (n=6),  water  changes,  observed  in daily  in urine  and  reduce  intake  of  increase  determined  this  account  day  o f withdrawal.  animals i n each  significant  altered  and  drastically  water.  no  i n water  i n t h e morphine o r p l a c e b o p e l l e t  second  Nevertheless,  can  a  d e c r e a s e i n water  observed  the  and  and  i n the c u r r e n t  were  throughout  changes  b a l a n c e . D i a r r h e a (142),  intake  A s i d e from  sudden  other  of  discovery (143)  raised  endogenous  the neurohypophysis.  the of the  opioid  Administration  71  of  B-endorphin has  AVP  in  the  been shown t o  rabbit  (144).  innervation  i n the  AVP  enkephalin  and  dehydration control  (145)  of  AVP  e n k e p h a l i n s on hormones  the in  turn  opiate to  agonists*  explain  the  dependence  adenylate cyclase  cyclase  cyclic  was  and its  activity.  action  of  found  stable  on  AMP  the  during  target  the  compensating  cellular  proposed  dependence injected  actions  level  of  the  dependence  have been  theories  i s the  as  proposed physical change i n  (68).  daily  with  the  cyclic  Whole  of  brain  morphine f o r  been shown t o  the of  exert  formation i t may  be  maintenance of  a  nucleotide. binding  tolerance  has  and  homogenates 14  of  tolerance  e x i s t s that  receptor  mechanism of  of  formation  a c c e l e r a t i n g the  possibility  i n opiate a  has  on  administration  enhanced  AVP  these  facilitate  and  Acute  and  that  mechanisms i n t h e  of  the  have r e p o r t e d  development  c e l l s by  (146), t h e  Alteration been  of  endorphins  tolerance  An  p h y s i c a l dependence. S i n c e  of c y c l i c one  (60).  during  shown t o c a u s e a t r a n s i e n t s u p p r e s s i o n  adenylate AMP  activity  both  neurohypophyseal  can  theories  of these  that  concept  physical  of  of  enkephalin  fact  of the  the  and  mechanism One  the  e t a l . (79)  A number o f  (59).  morphine was  control  to  of  depleted  the  hormones  tolerance  release  peptides.  influence  Krivoy  neurohypophyseal  development of  these  neurohypophysis,  endogenous o p i a t e s . the  the  the  were  f u r t h e r strengthen by  the  presence  content  from  may  The  n e u r o h y p o p h y s i s and  secretion  Aside  stimulate  d a y s showed  physical  from a  also  rats  decrease  72  in  3  H-naloxone  f i n d i n g s by in  the  binding  Pert  and  number  of  analysis revealed presence of the  3  H-naloxone  presence brain  binding  sites  were d e t e c t e d .  the  a  the  affinity  injected  are  probably  quantities  of  by  the  have no  3  H-naloxone  temporal  binding  and  relationship  tolerance  to the  morphine a p p e a r s r a t h e r weak. P e r t that  enhancement of  after  morphine t r e a t m e n t ,  for  4  day  of  and on  the  (35).  receptor  the  maximal  development  receptor  of  However,  binding  necessarily  the whole  ruled  dependence. effect  out Both  on  the  rule  the  between  opiate  analgesic effect Snyder  binding  (69)  of  found  appeared same  2 hr level  other  hand, has  been shown  reaches  a peak on  the  Hence, the  enhancement o f o p i a t e  dependence.  Also,  receptor  be  remained a t the  p r o g r e s s i v e l y and  treatment  and  opiate receptor  days. Tolerance,  to increase  of  binding.  The receptor  to  of the  by  opiate  oxytocin  found  in  caused  and  were  washing  morphine.  n e u r o h y p o p h y s e a l hormones can  AVP  the  interference  as a p o s s i b l e mechanism of t o l e r a n c e and  to  morphine i n t h e  homogenate. D i r e c t i n t e r f e r e n c e o f  binding  Scatchard  increase  the  the  changes  due  repeated  progressive  by  minute  likely  The  suggested  to  significant  changes are agonist.  This  binding  of  contrast  no  caused  changes i n r e c e p t o r  In  (69),  that  affinity.  VI).  Snyder  a competitive  homogenate  receptor  (Table  appearance  binding  occured  tolerance  lack  and  tolerance  out  the  of  third maximal  long  • and  physical  of c o r r e l a t i o n  in  development  does  possible  before  involvement  opiate not of  the  73  opiate  receptors..It i s highly  receptor brain.  affinity  or  binding  Such a l t e r a t i o n s may  probable  sites only  that  occur  occur  assessment  Hence, t h e y in  may  these  the  kidneys.  24  hr  excretion  the  has  hemoglobin  to t h e  Regional  small  skeletal  implantation  in  human  sedative  effect  a l . (48),  may  that  study  is  of  as  of  Crude not  be  in  the  morphine  on  from  a few  rats  a morphine p e l l e t .  drug  The  from n a r c o t i c addicts a  This  use  (51).  The  combination symptom  by  likely  of  i s quite  Schreiber  the be  drug  may the  be  animal  (52)..  addict,  be  of  any due  The  as  the  caused  by  the  under  the  present  proposed  adulterants. t o the  of  is  morphine  inert  in  cause  possibility  adulterants  excluded.  i s devoid  rhabdomyolysis  the  m o r p h i n e . . The  i s c a u s e d by by  brain*  of  observed  (48).,  and  immobilization  present  action  Rhabdomyolysis  used  binding  n e c r o s i s or r h a b d o m y o l y s i s were f o u n d  prolonged  rhabdomyolysis  dependence.  encountered  syndrome d e s c r i b e d  (51)  myoglobinuria..  et  the  phenomenon  s e r i e s i s the  crush  s i g n s measured i n  changes.  myoglobin  patients  heroin  of  been c h a r a c t e r i z e d as  and  structures  whole b r a i n homogenate, may  reported  pigmentation  the  examining the  o f d a r k brown u r i n e r e s u l t i n g  been  similar  by  Dark brown u r i n e was  after  regionally in  physical  structures  interesting  implantation  and  be d e t e c t e d  as  such  One  some  only  such  able to detect  has  tolerance  specific  preparations,  pellet  of  in  in brain  r e s p o n s i b l e f o r parameters or b e h a v i o r a l the  changes  by  used The  that  in  the  Richter in  the  likelihood  binders  used  in  74  the  processing  Control  whether  possible It  use  predisposes the  observation  does  possibility  implanted  animals.  chronic  link  is  of  interest  improves o r  of  renal  though to determine stabilizes  with  pellets  still  excluded.  was  and  the  made never  questionable  renal  i n some  disease. (48-51)  heroin  conclusively  other c o m p l i c a t i o n s a s s o c i a t e d with of  with  studies  renal disease  onset  be.  n a r c o t i c d r u g s can  onset  however,  t h a t the  It  of  also  myoglobinuria  supported  between  not;  may  m a t e r i a l s , yet  these  the  pellets  were  of such  in  unknown way current  the  animals  exclusively observed  of  on  be  out due  a d d i c t i o n . I t would  whether t h e withdrawal  a  addiction.  rule  disease  The  renal  of the  the to be  disease drug.  75  CONCLUSION  It has  i s clear that  morphine  an a n t i d i u r e t i c e f f e c t .  partially  responsible  The r e l e a s e  f o r the  f o r AVP r e l e a s e , however,  It  possible  hypothalamic  that  hypotensive  effect  of  acts  the  influence  application  o f morphine d i r e c t l y  drug  on t h e r e l e a s e  can  equally  observed  likely  on  cardiovascular  and  a  by  the  i s mediated  hypotension  interest  that  to  renal  effects examine  the output  When g i v e n neurohypophyseal  stores  by AVP  depletion  a decrease i n food release  morphine,  due  physical animal  The  dependence to  adapt  of  some It  In  the. resulting view  i t would  of  the  be  of  vasculature  depleted  depletion,  days.  The  due t o d e h y d r a t i o n intake..  t o the d i r e c t a c t i o n  hypothalamo-neurohypophyseal system possibility.  culture of  release.  morphine  lasted f o r 3  and water  The  constituents.  o f AVP. T h i s  i s partially  a  of the a n t i d i u r e s i s  f u n c t i o n . ..  chronically,  was t r a n s i e n t and o n l y this  on AVP  effects  urinary  exert  may p r o v i d e  i t s e f f e c t s on t h e r e n a l  of various  the the  hormone.  t o an i n v i t r o  portion  of  also  of the  c l u e t o t h e d i r e c t e f f e c t of the drug  on  However,  h y p o t h a l a m o - n e u r o h y p o p h y s e a l complex  is  questionable.  directly  cells.  substantial  the  o f AVP i s a t l e a s t  remains  morphine  neurosecretory  acutely  a n t i d i u r e s i s . The a c t u a l  stimulus i s  administered  however, cause  of  initiated  Potentiation  o f the drug  i s an  the  of  on t h e  equally  likely  s u b s e q u e n t d e v e l o p m e n t o f t o l e r a n c e and on to  morphine the  effects  presumably  allows  the  o f t h e d r u g by e i t h e r  76  decreasing  the  biosynthetic abruptly be  rate  rate.  withdrawn  of  secretion  Depletion  observed  on  AVP  release  hyperactivity depletion  of  during  unsettled.  increasing  as  the  sffect  well  CNS.  as  The  to  the  and  secretion  this  problem,* F u r t h e r m o r e , i f t h e d e p l e t i o n  augmented r e l e a s e determine  the  possibility systemic and  o f the peptide  o f AVP,  eventual  that  fate  morphine t r e a t m e n t  AVP  remains  biosynthetic some l i g h t t o  was due t o t h e  of  interest  to  o f t h e hormone. T h e r e i s a  also  duplicated  of  not  to various  opiate  as r e p o r t e d  in  this  only CNS  homogenates  severely  the r e c e p t o r .  facilitate: interfering receptor  the  receptor  by P e r t  study.  minute q u a n t i t i e s of t h e drug  to  be  elaborated  but  of  to  the  structures  t h e CSF. Enhancement  not  i t would  i t may be  circulation  may shed  can  generalized  cause  the  was  and water  and w i t h d r a w a l  S i m u l t a n e o u s measurements o f rates  animals  of s a l t  actual  morphine t r e a t m e n t  the  when t h e d r u g  from p h y s i c a l l y dependent  a t t r i b u t e d t o the stimulatory  loss  or  (69) was  I t was c o n c l u d e d  that the  left  The p o s s i b i l i t y  directly  was j u d g e d  with  and S n y d e r  in  the  affected the binding  development  binding  of  that  AVP  morphine  with the b i n d i n g t o be u n l i k e l y . .  whole  brain  of H-naloxone 3  and  oxytocin  tolerance  of t h e drug  to  by the  77  BIBLIOGRAPHY  I.  Eckenhoff, J. E . and S. . R.. Oech. The e f f e c t s o f narcotics and antagonists upon respiration and circulation in man. C l i n * P h a r m a c o l . E x p t l . T h e r a p . 1:483, 1960.  2..  Gyang, E. A. and H. W. Kosterlitz. Agonist and antagonist actions of morphine-like drugs on t h e guinea-pig isolated ileum. Brit. J. Pharmacol. 27: 514, 1966.  3.  Kornetsky, C. P h a r m a c o l o g y - d r u g s A f f e c t i n g New Y o r k , John W i l e y & Sons, 1976.  4. .  Cicero, T. J . and E. . R. Meyer. . Morphine pellet implantation in rats: quantitative assessment of tolerance and dependence*. J . , P h a r m a c o l . E x p t l . .. T h e r a p . 184:404, 1973.  5.  Hill, H. , C. Kornetsky, H. F l a n a r y and A.., W i k l e r . E f f e c t s o f a n x i e t y and morphine on d i s c r i m i n a t i o n of intensity of painful stimuli. J. Clin. Invest. 31: 473, 1952.  6.  Urquhart, J . and C. C. L i . Dynamic testing modeling of adrenocortical secretory function. N. Y. A c a d . . S c i . 156:756, 1969.  7.  Kokka, W. , J . F. , G a r c i a and H. W. Elliot* Growth hormone and ACTH s e c r e t i o n : e v i d e n c e f o r an i n v e r s e r e l a t i o n s h i p i n r a t s . E n d o c r i n o l o g y . 90:735, 1972.  8. '  F r e n c h , E. D. , J . F. G a r c i a and R. George. , Acute and chronic morphine effects on plasma c o r t i c o s t e r o i d s and g r o w t h hormone i n the cat. Psychoneuroendocr. 3:237, 1978.  9..  Gibson, A., M. G i n s b u r g , M. H a l l and S. L . . H a r t . The e f f e c t s of o p i a t e r e c e p t o r a g o n i s t s and antagonists on t h e s t r e s s - i n d u c e d s e c r e t i o n of c o r t i c o s t e r o n e i n mice. B r i t . J . P h a r m a c o l . 65:139, 1979.  Behavior.  and Ann.  10... T o l i s , G. , J . H i c k e y and H. Gujda. Effects of m o r p h i n e on serum growth hormone, C o r t i s o l , p r o l a c t i n and thyroid stimulating hormone i n man. J . C l i n . E n d o c r . Metab..41:797, 1975. II.  H a r t , I . C. and A. T. Cowie. Effect of morphine, naloxone and an e n k e p h a l i n a n a l o g u e on p l a s m a growth hormone, p r o l a c t i n , i n s u l i n and t h y r o x i n e i n goats. J . E n d o c r . 77:P 16, 1 978.  78  12.  L a i , H., W. . Brown, R. Drawbaugh, M. Hayes and G. Brown. E n h a n c e d p r o l a c t i n i n h i b i t i o n w i t h haloperidol and m o r p h i n e . L i f e S c i . . 2 0 : 1 0 1 , 1977.  13..  F e r l a n d , L . , G. S. K l e d z i k , L. Cusan and F. . L a b r i e . . Evidence for a role of e n d o r p h i n s i n s t r e s s - and s u c k l i n g - i n d u c e d p r o l a c t i n r e l e a s e i n t h e r a t . Molec. . C e l l . . E n d o c r . 12:267, 1978*  14.  M e l t z e r , H. Y. , R. J. Miller, R. G. Fessler, M. S i m o n o v i c and V. S. Fang. E f f e c t s of enkephalin a n a l o g u e s on p r o l a c t i n release in rat. Life Sci. 22: 1931, 1978. .  15.  Hang, C , V. Chang and R. T. T. Yeung. The e f f e c t s o f heroin addiction on p i t u i t a r y - t e s t i c u l a r function. C l i n . . E n d o c r . . 9 : 455, 1978.  16.  G a u l d e n , E . C., D. C. L i t t l e f i e l d , 0. E. P u t o f f and A. L. . S e i v e r t . Menstrual abnoemalities associated w i t h h e r o i n a d d i c t i o n . Amer. J . O b s t . Gynec. 90:155, 1964.  17.  I n t u r r i s i , C. E. and J . M. F u j i m o t o . S t u d i e s on t h e antidiuretic action o f morphine i n the r a t . J. P h a r m a c o l . 2:301, 1968.  18.  G i a r m a n , N. J . and G. A. C o n d o u r i s . The a n t i d i u r e t i c a c t i o n o f m o r p h i n e a n d some of i t s analogs. Arch. I n t r l . Pharmacodyn. 97:28, 1954.  19..  Schnieden, H. ..and E. K. Blackmore. Effect n a l o r p h i n e an t h e a n t i d i u r e t i c a c t i o n o f m o r p h i n e r a t s and men. B r i t . J . P h a r m a c o l . 10:45, 1955.  20.  Papper, S. and E. M. Papper.. The effects of p r e a n e s t h e t i c , a n e s t h e t i c and p o s t o p e r a t i v e d r u g s on r e n a l f u n c t i o n . . C l i n . P h a r m a c o l . T h e r a p . 5:205, 1964.  21.  De Bodo, R. C. The a n t i d i u r e t i c a c t i o n o f morphine and i t s mechanism. J . Pharmacol. Exptl. Therap. 82:74, 1944..  22.  Boyd, L . J . and D. S c h e r f . The e f f e c t o f s e d a t i v e s on d i u r e s i s . Med. C l i n . . N. Amer. 24:869, 1940...  23.  Marchand, C., D i u r e t i c and antidiuretic e f f e c t of morphine s u l f a t e i n r a t s . Proc. Soc. Exptl. Biol. Med..133:1303, 1970.  24.  Zelis, R. , E. J . Mansour, R. J . Capone and D. T. Mason. The c a r d i o v a s c u l a r e f f e c t s of morphine. The peripheral capacitance and resistance vessels in human s u b j e c t s . J . C l i n . I n v e s t . 54:1247, 1974.  of in  79  25.  Gomes, C. , T. H. S o r e n s o n and G. T r o l i n . . E f f e c t s of morphine on c e n t r a l catecholamine turnover, blood pressure and h e a r t rate in the rat. Naunyn Schniedebergs A r c h . P h a r m a c o l . . 2 9 3 : 1 4 1 , 1976.,  26.  Gomes, C , T. H. S o r e n s o n and G,. T r o l i n . E v i d e n c e f o r involvement of c e n t r a l n o r a d r e n e r g i c neurones i n t h e c a r d i o v a s c u l a r d e p r e s s i o n i n d u c e d by morphine i n t h e r a t . J . N e u r a l Transm. 39:33, 1976.  27.  Feldberg, W. and E . Wei.. The c e n t r a l o r i g i n and mechanism o f c a r d i o v a s c u l a r e f f e c t s o f morphine as revealed by n a l o x o n e i n c a t s . J . P h y s i o l . 272:P99, 1977.  28.  G i l m o r e , J . P. C o n t r i b u t i o n o f b a r o r e c e p t o r s to the c o n t r o l o f r e n a l f u n c t i o n . . C i r c . Res. 14:301, 1964.  29.  Korner, P. I. C o n t r o l of blood flow to s p e c i a l v a s c u l a r areas: b r a i n , kidney, muscle, skin* liver and i n t e s t i n e . _ I n : MTP I n t e r n a t i o n a l Review Of S c i e n c e , e d i t e d by Guyton, A. C. and C. E. . J o n e s . London, B u t t e r w o r t h s , 1974, pp. 123-162.  30.  Robertson, G. L. , E . A. Mahr, S. A t h a r and T. S i n h a . D e v e l o p m e n t and c l i n i c a l a p p l i c a t i o n o f a new method for the radioimmunoassay o f a r g i n i n e v a s o p r e s s i n i n human p l a s m a . J . C l i n , . I n v e s t . 52:2340, 1973. .  31.  G r e e n , J . F. , A. P. J a c k s o n and G.. P a r s o n s . The effects o f morphine on t h e m e c h a n i c a l p r o p e r t i e s o f the s y s t e m i c circulation i n t h e dog.. C i r c . Res. 42:474, 1978.  32.  Handley, C.. A. and A. D. K e l l e r . Changes i n r e n a l f u n c t i o n p r o d u c e d by morphine i n n o r m a l dogs and dogs w i t h d i a b e t e s i n s i p i d u s . J . P h a r m a c o l . . 9 9 : 3 3 , 1950.  33,.  Wei, E . and E . L . Way. A p p l i c a t i o n of the pellet implantation technique for the assessment of t o l e r a n c e and p h y s i c a l dependence i n t h e r o d e n t . I n : Methods i n N a r c o t i c s R e s e a r c h , e d i t e d by E h r e n p r e i s , S. and A. N e i d l e . New York, Marcel Dekker, I n c . , 1975, pp. 243-260.  34.  Blasig, J. , A. Herz, K. R e i n h o l d and S. Z i e g l g a n s b e r g e r . Development o f p h y s i c a l dependence on morphine i n respect t o time and d o s a g e and quantification of the precipitated withdrawal syndrome i n r a t s . Psychopharm. 33:19, 1973.  80  35.  Halbach, H. and N. . B. Eddy. Tests for addiction ( c h r o n i c i n t o x i c a t i o n ) of m o r p h i n e t y p e * B u l l * , W . H. 0. 28:139, 1963.  36.  Wiklar, A., W. R. Martin, F. T. P e s c o r and C;.G. Eades. F a c t o r s regulating oral consumption of an opioid (etonitazene) by morphine-addicted rats, P s y c h o p h a r m . 5: 55, 1963.  37.  G i b s o n , R. D. and J . E. T i n g s t a d s . F o r m u l a t i o n of a morphine implantation pellet suitable for tolerancep h y s i c a l dependence s t u d i e s i n mice. J . Pharm. , S c i . 59:426, 1970.  38..  Way, E. L., H.. H. Loh and F. Shen. S i m u l t a n e o u s q u a n t i t a t i v e assessment of morphine tolerance and physical dependence. J. Pharmacol. E x p t l . . Therap. 167:1 , 1969.  39.  Himmelsbach, C. K. Clinical studies of addiction: physical dependence, withdrawal r e c o v e r y . A r c h . . I n t e r n . Med. 69:766, 1942.  40.  Martin, W. R. and D. R. Jasinski. Physiological p a r a m e t e r s o f m o r p h i n e dependence i n man - t o l e r a n c e , early abstinence, protracted abstinence. .J..Psychait. , Res. 7:9, 1969.  41.  Martin, W. . R. , D. R. J a s i n s k i , J . D. S a p i r a , H. . G. F l a n a r y , 0. A. K e l l y , A. K. Thompson and C..R..Logan. The r e s p i r a t o r y e f f e c t s o f morphine d u r i n g a c y c l e o f dependence. J . Pharmacol. Exptl. T h e r a p . . 162:182, 1968. .  42.  Chance, W.. T..and J. A. Rasecrans. I n h i b i t i o n of drinking by intrahypothalamic administration of m o r p h i n e . . N a t u r e . 270: 167, 1977..  43.  Holmes, J. S., M, K, C a r t e r and J . M. F u j i m o t o . P o l y d i p s i a and p o l y u r i a d u r i n g c h r o n i c a d m i n i s t r a t i o n o f l e v o r p h a n o l t o r a t s . P r o c . Soc. E x p t l . B i o l . Med. 99:319, 1958.  44.  M a r c h a n d , C. and G* D a v i s . D i u r e t i c e f f e c t of c h r o n i c morphine treatment in rats. J . . Pharmacol. E x p t l . . T h e r a p . 162:331, 1968.  45..  Rao, T. K. S., A. D. N i c a s t r i and E. A. Friedman* Natural h i s t o r y of h e r o i n a s s o c i a t e d nephopathy. New E n g l . „ J . Med. 290: 19, 1974.  drug and  81  46.  T r e s e r , g , . , C. C h e r u b i n , E. T. Lomergan, N. _ Y o s h i z a w a , V. V i s w a n a t h a n , A. A. Tannenberg, D. Pompa and K. Lange* Renal l e s i o n s i n n a r c o t i c a d d i c t s . Amer. J . Med. 57:678, 1974.  47.  G r i s h m a n , E. and J . C h u r g . Focal glomerulosclerosis i n n e p h r o t i c p a t i e n t s : an e l e c t r o n m i c r o s c o p i c s t u d y . . K i d n e y I n t r l . 7: 1 11, 1975.  48..  Richter, R. W., Y. B. C h a l l e n o r , J . P e a r s o n , L. J . Kagen, L. L. H a m i l t o n and W. H. Ramsey.. Acute myoglobinuria associated with heroin addiction. J. Amer.,Med. A s s o c . .216:1172, 1971.  49.  Avram, M. M., M. I a n c u and S. Weiss.. Heroin Usage Nephropathy Subclinical To End Stage.Nephrotic Syndrome* Proc* . F i f t h Ann. .Meet. Amer. Soc* N e p h r o l . , Washington, 1971.  50..  D a v i s , J . S. and J . T. L i e . E x t r a c e l l u l a r glomerular m i c r o p a r t i c i e s i n n e p h r o t i c syndrome o f h e r o i n u s e r s * A r c h . P a t h o l * 99: 278, 1975.  51.  Klock, J . and M. J . S e x t o n . R h a b d o m y o l y s i s and myoglobinuric r e n a l failure following heroin C l i f . Med. 119: 5, 1973.  52.  Schreiber, S. N. , M. R. Liebowitz; L. H. B e r n s t e i n and S. Srinivasan. Limb compression and renal impairment (crush syndrome) complicating n a r c o t i c o v e r d o s e . New E n g l . J . . Med. 284:368, 1971.  53...  Akmal, M. , D. A. Goldstein, N. Telfer, E. W i l k i n s o n and S. G. Massry. Resolution of muscle calcification in rhabdomyolysis and acute renal f a i l u r e . Ann. I n t e r n * Med..89:928, 1978.  54.  Knochel, J. P., C. Barcenas, J . R. C o t t o n * T. J . F u l l e r , R . . H a l l e r and N. W. C a r t e r . . H y p o p h o s p h a t e m i a and r h a b d o m y o l y s i s . J . C l i n . I n v e s t . 62:1240, 1978.  55.  Hughes, J., T. . W. Smith, H..W. K o s t e r l i t z , L. . A. . Fothergill, B. . A. Morgan and H. . R. . M o r r i s . . Identification o f two r e l a t e d p e n t a p e p t i d e s f r o m t h e b r a i n with potent o p i a t e agonist a c t i v i t y . . Nature. . 258:577, 1975. .  56.  Goldstein, A. Opioid peptides (endorphins) p i t u i t a r y and b r a i n . S c i e n c e . 193: 1081, 1976..  57.  L a m p e r t , A. , M. . N i r e n b e r g and W. A. . K l e e . . T o l e r a n c e and dependence e v o k e d by endogenous o p i a t e p e p t i d e s . P r o c . . N a t l . . Acad. , S c i . U. S. .A. 73: 3165, 1976.  acute use.  in  82  58.  Wei, like  E. and H. L o h . Physical dependence p e p t i d e s . S c i e n c e . 193:1262, 1976.  on  opiate  59.  Cochin, J. Possible mechanisms i n development of t o l e r a n c e . P r o c . Soc. E x p t l . B i o l . . M e d . 29:19, 1970..  60.  C o l l i e r , H. 0. J . , D. L . Francis, W. J. McDonaldGibson, A.. C. . Boy and S..A..Saeed. P r o s t a g l a n d i n s , c y c l i c AMP and t h e mechanism of opiate dependence.. L i f e Sci..17:85, 1975.  61.  Traber, J . , K. F i s h e r , S. L a t z i n and B. Hamprecht. Morphine antagonizes action of prostaglandins in n e u r o b l a s t o m a x g l i o m a h y b r i d c e l l s . N a t u r e . 25.3: 120, 1975.  62.  Traber, J . , E. G u l l i s and B. Hamprecht. I n f l u e n c e o f opiates on the level of adenosine 3',5'-cyclic monophosphate i n n e u r o b l a s t o m a x g l i o m a h y b r i d c e l l s . L i f e S c i . .16: 1863, 1975.  63.  Kennedy, B. L. and T. C. W e s t . . E f f e c t o f m o r p h i n e on e l e c t r i c a l l y - i n d u c e d r e l e a s e of autonomic mediators in the r a b b i t s i n o a t r i a l node. J . P h a r m a c o l . E x p t l . T h e r a p . 157:149, 1967.  64.  B h a r g a v a , R. N. .and G. A. M a t w y s h y n . . B r a i n serotonin t u r n o v e r and morphine t o l e r a n c e - d e p e n d e n c e i n d u c e d by multiple injections in the r a t . Eur. J..Pharmacol. 44: 25, 1977,. .  65.  S i m a n t o v , R. and enkephalin in 262:505, 1976.  66.  K o s t e r l i t z , H. W. and H. Hughes. Some t h o u g h t s on t h e s i g n i f i c a n c e of e n k e p h a l i n , the endogenous ligand. L i f e S c i . 17:91, 1975.  67.  M a l f r o y , B. , J . ,P. S w e r t s , A. Guyon, B. P. Rogues and J. Z. . S c h w a r t z . . H i g h - a f f i n i t y e n k e p h a l i n - d e g r a d i n g peptidase in brain i s increased after morphine. N a t u r e . , 276: 523, 1978.  68.  Collier, H. 0. r e c e p t o r s . Adv.  69,.  P e r t , C. B. and S. H. S n y d e r . . O p i a t e r e c e p t o r b i n d i n g enhancement by opiate administration in vivo. Biocti em. . P h a r m a c o l . 25: 847, 1976.  S.,H. Snyder. Elevated levels of morphine-dependent rats. Nature..  J . Tolerance, physical Drug Res. 3:17, 1966.  dependence  and  83  70.. Cohen, M., A. S. K e a t s , W. A. K r i v o y and G. Omgar. E f f e c t o f a c t i n o m y s i n D on morphine t o l e r a n c e . Proc. Soc. E x p t l . . B i o l . . Med. (New York) 119: 381, 1965. 71.  Caldwell, J . and P. S. Sever. The biochemical pharmacology of abused drugs. I I I . C a n n a b i s , opiates and synthetic narcotics.. Clin. Pharmacol. Exptl. T h e r a p . . 16: 989, 1974.  72.  Mark, R. Memory and Nerve C e l l C l a r e n d o n P r e s s , 1974.  73.  Matthies, H. Biochemical basis memory. L i f e S c i . 15:2017, 1974.  74.  Ader, R. passive 1972.  75.  D. , B. Bohus and De Weid, Memory deficits G r e i d anus, i n s i p i d u s . B r a i n Res. .85: 152,  76.  Van Ree, J. M. and D. De glycinamide (PLG) facilitate L i f e S c i . 19:1331, 1976.  77.  Krivoy, W. A., E. Zimmarmann and S. . Lande. F a c i l i t a t i o n o f d e v e l o p m e n t o f r e s i s t a n c e t o morphine a n a l g e s i a by d e s g l y c i n a m i d e - l y s i n e v a s o p r e s s i n . P r o c . N a t l . . Acad. S c i . U. S. A. 71:1852, 1974.  78..  De Weid, D. and W. H. G i s p i n . I m p a i r e d d e v e l o p m e n t o f t o l e r a n c e t o morphine a n a l g e s i a i n r a t s w i t h d i a b e t e s i n s i p i d u s . .Psychopharm. 46:27, 1976.  79,.  L a n d e , S., J . , B. F l e x n e r and L. B . . F l e x n e r . . E f f e c t o f corticotrophin and d e s g l y c i n a m i d e - l y s i n e v a s o p r e s s i n on s u p p r e s s i o n o f memory by puromycin. Proc. Natl. Acad. . S c i . . (Wash.). . 69: 558. 1972.  80.  Newmark, 1977.  81.  Tata, 269:,  82.  Williams, L. T. and R. J . L e f k o w i t z . T h y r o i d hormone r e g u l a t i o n o f B - a d r e n e r g i c r e c e p t o r number. J . . B i o l . Chem..252:2787, 1977.  Connections,. of  Oxford,  learning  and  and D. De Weid. E f f e c t s , o f vasopressin on avoidance l e a r n i n g . Psychon. S c i . 29:46,  R e c e p t o r s and  J . R. M o d u a l t i o n 1977..  T j . B. in rats 1975.  Van with  Wimersma diabetes  Weid. Prolyl-leucylmorphine dependence. .  hormones.  o f hormone  Nature..270:12,  receptors.  Nature.  84  83.  Yates, F . . E . , S. R u s s e l , M. F. D a l l m a n * G. A. Hedge, S. M. McCann and A. P. S. D h a r i w a l . P o t e n t i a t i o n by vasopressin of corticotropin release induced by c o r t i c o t r o p i n - r e l e a s i n g factor. Endocrinology. 88:3, 1971.  84.  Gillies, G. and P. J . Lowry. P e r f u s e d r a t i s o l a t e d anterior pituitary cell column as bioassay for f a c t o r (s) c o n t r o l l i n g r e l e a s e o f a d r e n o c o r t i c o t r o p i c validation of a t e c h n i q u e . E n d o c r i n o l o g y . 103:521, 1978.  85.  G i s p i n , W. Wh. , J. Buitelaar, V. M. Wiegant, L. T e r e n i u s and D. De Weid. I n t e r a c t i o n between ACTH fragments, brain opiate receptors and morphinei n d u c e d a n a l g e s i a . E u r . J . P h a r m a c o l . 39:393, 1976.  86.  De Weid, D. 1977.  87.  George, J . M. and M. Jacobowitz. Localization vasopressin in discrete areas of the h y p o t h a l a m u s . B r a i n Res. 93:363, 1975.  88..  G e o r g e , J . M. , S. . S t a p l e s and B. content of microdissected areas E n d o c r i n o l o g y . 98:1430, 1976.  89.  B u i j s , R. M. I n t r a - and e x t r a h y p o t h a l a m i c v a s o p r e s s i n and o x y t o c i n pathways i n t h e r a t pathways to the limbic system, medulla oblongata and s p i n a l c o r d . C e l l T i s s . . Res. . 192: 423, 1978.  90.  K r e j c i , I . , B. Kupkova, J . Metys, T. B a r t h and K. J o s t . . V a s o p r e s s i n a n a l o g u e s : s e d a t i v e p r o p e r t i e s and p a s s i v e avoidance behavior in the r a t s . . Eur. J. P h a r m a c o l . 56:347, 1979.  91.  Nicoll, R. A. .and J . L. B a r k e r . The p h a r m a c o l o g y o f r e c u r r e n t i n h i b i t i o n i n the s u p r a o p t i c n e u r o s e c r e t o r y s y s t e m . B r a i n Res. 35:501, 1971,.  92.  Moss, R. L., R. E.. J , . D y b a l l and B. A. Cross.. Excitation of antidromically identified n e u r o s e c r e t o r y c e l l s of t h e p a r a v e n t r i c u l a r nucleus by o x y t o c i n a p p l i e d i o n t o p h o r e t i c a l l y . E x p t l . N e u r o l . 34: 95, 1972. .  P e p t i d e s and  behavior.  Life  S c i . 20:195, of rat  M. Marks.. O x y t o c i n of r a t hypothalamus.  93. , S c o t t , D. E. and W. K. P a u l l * C o r r e l a t i v e s c a n n i n g t r a n s m i s s i o n e l e c t r o n m i c r o s c o p i c examination of the perinatal rat b r a i n . . I. The t h i r d v e n t r i c l e . C e l l T i s s . .Res. 190: 317, 1978.  85  94.  Dogterom, J . , T j . B. Van Wimersma G r e i d a n u s and D. De Weid. V a s o p r e s s i n i n c e r e b r o s p i n a l f l u i d and plasma of man, dog and rat. Amer. J . P h y s i o l . 234:E463, 1978.  95.  De Weid, D. Long term e f f e c t o f vasopressin on the maintenance of a conditioned avoidance response i n r a t s . . N a t u r e . 232:58, 1971 .  96.  Van Wimersma G r e i d a n u s , T j . B., J . Dogterom and D. De Weid. Intraventricular administration of antivasopressin antiserum i n h i b i t s memory c o n s o l i d a t i o n i n r a t s . L i f e S c i . 16:637, 1975.  97.  M e i t e s , J . , J . F. B r u n i , D. A. Van Vugt and A. F. Smith. Relation of endogenous o p i o i d p e p t i d e s and morphine to neuroendocrine functions. Life Sci.. 24: 1325, 1979.  98.  Verney, E. B. The antidiuretic hormone and f a c t o r s which d e t e r m i n e i t s r e l e a s e . P r o c . R o y a l (B) 135: 25, 1947.  99.  R o b e r t s o n , G. L. and S. Athar. The blood osmolality and blood volume plasma v a s o p r e s s i n i n man. J. Clin. 42:613, 1976.  100.  V a l t i n , H. and H. A. S c h r o e d e r . . F a m i l i a l h y p o t h a l a m i c diabetes insipidus in rats (Brattleboro strain).. Amer. J . P h y s i o l . 206:425, 1965.  101.  Domino, E. F. and A. Wilson. Effect of narcotic agonists and a n t a g o n i s t s on r a t b r a i n a c e t y l c h o l i n e . J..Pharmacol..Exptl. Therap..184:18, 1973.  102.  M a r t i n , W. R., A. Wikler, C. G.. Eades and F. Pescor.. Tolerance to and physical dependence m o r p h i n e i n r a t s . Psychopharm. 4:247, 1963..  103.  B i e , P. and N. A. T h o r n . In vitro studies of release mechanism for vasopressin in rats. Studies of the possible release of hormone h y p o t h a l a m i c s l i c e s . A c t a E n d o c r . 56:139, 1967.  104.  Pert, C. B..and S. Snyder. Opiate demonstration i n nervous t i s s u e . Science.. 1973.  105.  Lowry, 0., N.. R o s e n b r o u g h , A. P r o t e i n measurement w i t h Folin B i o l . ,Chem. 193: 265, 1951.  the Soc.  interaction of in regulating E n d o c r . . Metab.  T. on the II. from  receptor: 179:1011,  F a r r and R. R a n d a l l . phenol reagent. J.  86  106..Pert, C. B. and S. Snyder.. P r o p e r t i e s of o p i a t e r e c e p t o r b i n d i n g i n r a t b r a i n . Proc. Natl..Acad. S c i . 0. S. A. 70:2243, 1973. 107.  P e r t , C. B..and S. S n y d e r . . O p i a t e r e c e p t o r b i n d i n g o f a g o n i s t s and a n t a g o n i s t s a f f e c t e d differentailly by s o d i u m . M o l e c u l a r P h a r m a c o l . 10:868, 1974.,  108. B u r g e t , D . „ W . and N. W i l s o n . , A p p l i c a t i o n o f a f f i n i t y chromatography t o radioimmunoassay of antidiuretic hormone. In: Proceedings of the Canadian Chromatography Conference ( i n p r e s s ) , edited by M. B h a t n a g a r . New Y o r k , M a r c e l D e k k e r I n c . , 1978. 109.  Weitzman, E. E. and D.. A. Fisher. Mono- and d i i o d i n a t e d a r g i n i n e v a s o p r e s s i n : a n t i b o d y and membrane b i n d i n g s t u d i e s . . I n : The F i f t h I n t e r n a t i o n a l C o n g r e s s Of E n d o c r i n o l o g y . A b s t r a c t no. 185, 1976. p . 75.  110.  Greenwood, F. C , W. M. .Hunter and J . S. G l o v e r . The preparation o f i 3 * i l a b e l l e d human growth hormone o f high specific radioactivity. B i o c h e m . J . 89:114, 196 3.  111..Goodfriend, T. . L. , L. L e v i n e and G. D. Fasman. A n t i b o d i e s t o b r a d y k i n i n and a n g i o t e n s i n : a use o f c a r b o d i i m i d e i n i m m u n o l o g y . S c i e n c e . 144:1344, 1964,. 112. K e e l e r , R..and N. W i l s o n . V a s o p r e s s i n c o n t a m i n a t i o n as a cause o f some apparent renal actions of p r o l a c t i n . Can. J . P h y s i o l . 54:887, 1976. 113.  Rodbard, D., W. B r i d s o n and P. L. R a y f o r d . R a p i d calculation of radioimmunoassay r e s u l t s * , J . Lab. C l i n . Med. 74:770, 1969.  114. W i l s o n , N. and V. Y. Greenhouse. l o d i n a t i o n and p u r i f i c a t i o n o f o x y t o c i n . J . C h r o m a t o g . . 118:83, 1976.. 115.  Scatchard, molecules 1949..  G. The a t t r a c t i o n s o f p r o t e i n s f o r small and i o n s * Ann. N. Y. Acad. S c i . 51:660,  116. C z a c z k e s , J . . W., C. R. Kleeman and M, Koenig. Physiologic studies o f a n t i d i u r e t i c hormone by i t s d i r e c t measurement i n human plasma, J . C l i n . Invest. 43:1625, 1964. . 117.  Schrier, R. W. and T. Berl. a f f e c t i n g r e n a l water e x c r e t i o n . 292:81, 1975.  Nonosmotic factors New E n g l . . J . . Med.  87  118.  Millar, M. and A. M. Moses. Potentiation of vasopressin action by chlorpropamide in vivo.. E n d o c r i n o l o g y . . 8 6 : 1 0 2 4 , 1970.  119.  Schnermann, J . Physical forces and t r a n s t u b u l a r movement o f s o l u t e s and w a t e r . I n : K i d n e y And U r i n a r y Tract Physiology, edited by Thurau, K. London, B u t t e r w o r t h s , 1974, pp. 157-198..  120.  M c G i f f , J . C. and T. M. .Fasy. The r e l a t i o n s h i p o f t h e renal vascular activity of angiotensin I I to the autonomic nervous system. J . C l i n . I n v e t . . 44:1911, 1965. .  121. . L a r a g h , J . H., P. J . Cannon, C. J . B e n t z e l , A. M. . S i c i n s k i and J. I. Meltzer. Angiotensin II, norepinephrine and r e n a l t r a n s p o r t of e l e c t r o l y t e s and water i n normal man and in cirrhosis with • a s c i t e s . J . C l i n . I n v e s t . 42:1179, 1963. 122.  Banks, R. 0. Influence o f ADH on i n t r a r e n a l b l o o d flow d i s t r i b u t i o n i n diabetes insipidus d o g s and r a t s . P r o c . S o c . E x p t l . B i o l . Med. 151:547, 1976.  123.  Brenner, B. M. , W, M. Dean and C. . R. , R o b e r t s o n . , G l o m e r u l a r f i l t r a t i o n . .In: The K i d n e y , v o l . I , e d i t e d by B r e n n e r , B. M. and F. C. R e c t o r , J r . P h i l a d e l p h i a , W. B . , S a u n d e r s Co., 1976, pp. .251-271.  124.  S e l k u r t , E. E. C u r r e n t s t a t u s of renal circulation and related nephron function i n hemorrhage and experimental shock. I. Vascular mechanisms. Circ. Shock. 1:3, 1974.  125.  V a t n e r , S. F. E f f e c t s o f hemorrhage on r e g i o n a l b l o o d flow distribution i n dogs and primates. J . C l i n . . I n v e s t . 54:225, 1974..  126.  G i l l , J . R., J r . and A. G. T. Casper. Role sympathetic nervous sytem i n the r e n a l response h e m o r r h a g e . J . C l i n . I n v e s t . 48:915, 1969..  127.  Rector, J . Osgood and vasopressor f l o w . . Amer.  of to  B., J . H. Stein, W. H. Bay, R. W. T.. F. F e r r i s . E f f e c t o f hemorrhage and a g e n t s on distribution of r e n a l blood J . . P h y s i o l . 222:1125, 1972.  128..Barraclough, M. A. and N. F. J o n e s . The e f f e c t o f v a s o p r e s s i n on t h e r e a b s o r p t i o n o f sodium, potassium and urea by the renal t u b u l e s i n man. C l i n . S c i . 39:517, 1970.  88  129.  Pang, C. C. Y., W. C. W i l c o x and J . R. M c N e i l l . Time course of mesenteric vasodilatation following h y p o p h y s e c t o m y and the stopping of a vasopressin i n f u s i o n * Can. J . P h y s i o l . . P h a r m a c o l . 56:735, 1978.  130.  McNeill, J. R. , W. C. W i l c o x and C. C. Y. Pang. V a s o p r e s s i n and angiotensin: reciprocal mechanisms c o n t r o l l i n g m e s e n t e r i c c o n d u c t a n c e . Amer. J . . P h y s i o l . 232:H260, 1977.  131.  Fisher, R. D. , J. P. G r u n f e l d and A. .. C. . B a r g e r . . I n t r a r e n a l d i s t r i b u t i o n of blood flow in diabetes insipidus: role of ADH. Amer. J . P h y s i o l . ,219: 1348, 1970.  132.  P i c k f o r d , M. N e u r o h y p o p h y s i s and k i d n e y f u n c t i o n . The P i t u i t a r y G l a n d , v o l . 3, edited by Harris, W. and B. . T. Donovan. London, B u t t e r w o r t h s , 1966, 374-398.  133.  Jaffe, J. H. and W.R..Martin. Narcotic analgesics and a n t a g o n i s t s . In: The Pharmacological Basis of Therapeutics ( f i f t h ed.), edited by Goodman, L. S. and A. G i l m a n . New Y o r k , M a c M i l l a n P u b l . Co.,1975, pp. .245-283.  134.  Way, E. L. and T. K. A d l e r • B i o l o g i c a l d i s p o s i t i o n of m o r p h i n e and i t s s u r r o g a t e s - 1. Bull. W. . H. 0. . 25:227, 1961.  135.  Mullis, K. . B. , D. C. Perry, A. M. Finn, B. . S t a f f o r d and W. Sadee. Morphine persistence in rat brain and serum after s i n g l e doses. J. . Pharmacol. E x p t l . . T h e r a p . , 208:228, 1979.  136.  D i c k e r , S. E. and C. T y l e r . V a s o p r e s s o r and oxytocic activities of the p i t u i t a r y glands of r a t s , guinea p i g s and c a t s and of human fetuses. J. Physiol., 121:206, 1953.  In: C. pp.  137..Jones, C. W. and B. T. P i c k e r i n g . C o m p a r i s o n o f t h e effect of water deprivation and sodium chloride inhibition on the hormone content of the neurohypophysis of the rat. J. Physiol. 203:449, 1969. 138.  Ford, D. H., D. W e i s f u s e , M. L e v i and R. K. R h i n e . . A c c u m u l a t i o n o f H - l y s i n e by b r a i n and plasma i n male and f e m a l e r a t s t r e a t e d w i t h m o r p h i n e s u l f a t e . . Acta N e u r o l . . S c a n d . 50: 57, 1974. 3  89  139.  Young, T. K. and H• B. Van Dyke. Bepletion of v a s o p r e s s i n and o x y t o c i n i n the p o s t e r i o r l o b e of t h e p i t u i t a r y g l a n d o f t h e r a t . J . E n d o c r . 40:337, 1968.  140.  S c h w a r t z , W. B., W. B e n n e t t , S. C u r e l o p and F. C. Bartter. a syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone., amer. J . . Med. 23:529, 1957.  141.  Haldar, J. Independent release vasopressin during parturition P h y s i o l . 206: 723, 1970..  of in  oxytocin and the rabbit. J.  142.  Ho, A. K. S., C. A. R. Chen and M. J . withdrawal i n the r a t : assessment by of diarrhea and modification P h a r m a c o l o g i a . 18:9, 1979.  Kreek. Morphine quantification by ethanol.  143.  Simantov, R. and S. H. binding in the p i t u i t a r y 1 977.  Snyder., O p i a t e g l a n d . B r a i n Res.  receptor 124:178,  144. . Weitzman, R. E., D. A. F i s h e r , S. M i n i c k , N. L i n g and R. G u i l l e m i n . B-endorphin stimulates secretion of arginine vasopressin in vivo. Endocrinology. 101:1643, 1977. 1  145.  R o s s i e r , J . , E. B a t t e n b e r g , Q. P i t t m a n , A. Bayon, L. Koda, R. Miller, R. G u i l l e m i n and F. . Bloom. Hypothalamic enkephalin neurones may regulate the n e u r o h y p o p h y s i s . N a t u r e . 277:653, 1979.  146.  Orloff, J . and J . S. H a n d l e r . The r o l e 3',5»-phosphate in the action of hormone. Amer. J . Med. 42:757, 1967.  of adenosine antidiuretic  

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