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The effects of the acute administration of buprenorphine hydrochloride on the release of anterior pituitary hormones in the rat: Evidence for the involvement of multiple opiate receptors
Life Sciences, Vol. 37, pp. 1861-1868 Printed in the U.S.A.
Pergamon Press
THE EFFECTS OF THE ACUTE ADMINISTRATION OF BUPRENORPHINE HYDROCHLORIDE ON THE RELEASE OF ANTERIOR PITUITARY HORMONES IN THE RAT: EVIDENCE FOR THE INVOLVEMENT OF MULTIPLE OPIATE RECEPTORS Robert N. Pechnick l, Robert George 2 and Russell E. Poland Department of Pharmaeology School of Medicine, the Brain Research Institute and the L a b o r a t o r y of Neuroendoerinology University of California Los Angeles, CA 90024 and Division of Biological P s y c h i a t r y Harbor-UCLA Medical Center Torrance, California 90502 (Received in final form August 29~ 1985)
Summary Multiple opiate r e c e p t o r agonists and antagonists have been found to p r o d u c e different p a t t e r n s of anterior p i t u i t a r y hormone release. The p r e s e n t studies examined the p a t t e r n of anterior p i t u i t a r y hormone release p r o d u c e d b y b u p r e n o r p h i n e . The effects of the kappa agonist ethylketoeyclazoeine on t h y r o i d stimulating hormone release were also examined. Following b u p r e n o r p h i n e , serum levels of corticosterone and luteinizing hormone were not changed while growth hormone release was stimulated in a d o s e - d e p e n d e n t manner. Prolactin release was stimulated after the lowest dose of b u p r e norphine while the highest dose induced a fall in serum prolactin. Similar biphasic effects on t h y r o i d stimulating hormone were seen after either b u p r e n o r p h i n e or ethylketocyclazocine. The results provide s u p p o r t for the role of multiple opiate r e c e p t o r s in opiateinduced changes in anterior pituitary hormone release. B u p r e n o r p h i n e (BUP) is an opiate alkaloid with both agonist and antagonist activity that was classified in the dog as a partial mu agonist b y Martin et al. (1). In rodent antinocieeptive assays BUP is 25 - 40 times more potent than morphine following subcutaneous injection (2). However, the d o s e - r e s p o n s e relationship of BUP with r e s p e c t to analgesia has been found to be bell-shaped with the antinociceptive activity d e c r e a s i n g at h i g h e r doses after initial d o s e - d e p e n d e n t increases ( 2 , 3 , 4 ) . BUP also has significant opiate antagonist activity in that it can antagonize the analgesic activity of morphine as well as precipitate withdrawal in morphine-dependent subjects ( 2 , 5 , 6 ) . As with o t h e r opiate agonists, tolerance develops upon repeated administration ( 2 , 4 , 6 ) , however, little or no abstinence syndrome is seen following narcotic Ipresent address: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, School of Medicine, University of California, Los Angeles, California 90024. ~to whom r e p r i n t r e q u e s t s should be a d d r e s s e d . 0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.
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a n t a g o n i s t c h a l l e n g e o r a b r u p t w i t h d r a w a l in r a t s ( 7 ) , m o n k e y s ( 2 , 6 ) a n d man (5,8). In f u r t h e r c o n t r a s t to o t h e r m i x e d a g o n i s t - a n t a g o n i s t s BUP d o e s n o t p r o d u c e d y s p h o r i a (2) a n d h a s b e e n r e p o r t e d to p r o d u c e p o s i t i v e s u b j e c t i v e e f f e c t s a n d e u p h o r i a in h e r o i n a d d i c t s ( 5 , 9 ) . The unique pattern of activity o f BUP a l o n g with i t s low d e g r e e of t o x i c i t y ( i 0 ) h a s l e d to i t s s u g g e s t e d clinical use as an analgesic (ll), a s an a n t i d e p r e s s a n t ( 1 2 ) , a n d in t h e p h a r m a c o t h e r a p y of h e r o i n a d d i c t i o n ( 9 ) . T h e e f f e c t s o f t h e a d m i n i s t r a t i o n o f o p i a t e s on t h e r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s h a v e b e e n e x t e n s i v e l y s t u d i e d in t h e r a t ( 1 3 , 1 4 , 1 5 , 1 6 ) . T h e a c u t e a d m i n i s t r a t i o n o f mu o p i a t e a g o n i s t s c a u s e s i n c r e a s e s in t h e r e l e a s e o f A C T H , g r o w t h h o r m o n e ( G H ) , p r o l a c t i n ( P R L ) a n d d e c r e a s e s in l u t e i n i z i n g h o r m o n e (LH) a n d t h y r o i d s t i m u l a t i n g h o r m o n e ( T S H ) . When a d m i n i s t e r e d alone opiate antagonists produce a different pattern of release characterized by a fall in PRL a n d a r i s e in LH p r e s u m a b l y v i a t h e i n h i b i t i o n o f e n d o g e n o u s o p i o i d p e p t i d e s t h a t t o n i c a l l y c o n t r o l t h e r e l e a s e of t h e s e h o r m o n e s ( 1 7 , 1 8 , 1 9 ) . It h a s r e c e n t l y b e e n s h o w n t h a t t h e a d m i n i s t r a t i o n o f t h e p r o t o t y p e k a p p a o p i a t e a g o n i s t [ a s d e f i n e d b y M a r t i n et al. ( 1 ) ] e t h y l k e t o c y c l a z o c i n e (EKC) e l i c i t s a d i f f e r e n t p a t t e r n of r e l e a s e from t h a t s e e n following t h e a d m i n i s t r a t i o n o f t h e mu a g o n i s t m o r p h i n e ( 2 0 , 2 1 ) . It is o f i n t e r e s t to c h a r a c t e r i z e t h e p a t t e r n of a n t e r i o r p i t u i t a r y h o r m o n e r e l e a s e i n d u c e d b y BUP s i n c e BUP h a s b o t h mu a g o n i s t a n d a n t a g o n i s t a c t i v i t y a n d also s h o w s a c t i v i t y s u g g e s t i n g t h e involvement of kappa receptors (22,23,24). The comparison of the pattern of r e l e a s e s e e n a f t e r BUP a d m i n i s t r a t i o n with t h e p a t t e r n s seen after the a d m i n i s t r a t i o n o f mu a g o n i s t s , mu a n t a g o n i s t s a n d k a p p a a g o n i s t s p r o v i d e s an i n d i e a t i o n a s to how BUP is i n t e r a c t i n g with o p i a t e r e c e p t o r s . The purpose of t h i s s t u d y is to c h a r a c t e r i z e t h e p a t t e r n o f a n t e r i o r p i t u i t a r y h o r m o n e r e l e a s e i n d u c e d b y t h e a c u t e a d m i n i s t r a t i o n of BUP. T h e e f f e c t s of t h e a d m i n i s t r a t i o n o f m o r p h i n e s u l f a t e (MS) a n d EKC on t h e r e l e a s e of TSH will also b e d e s c r i b e d a n d c o m p a r e d with t h e r e s u l t s s e e n f o l l o w i n g t h e a d m i n i s t r a t i o n of BUP. Materials and Methods Male, S p r a g u e - D a w l e y r a t s (280-300 g) w e r e h o u s e d 6 p e r c a g e u n d e r a 12 h l i g h t - d a r k c y c l e ( l i g h t s on 0700-1900 h ) f o r 7 d a y s p r i o r to d r u g administration. T h e h o u s i n g r o o m was m a i n t a i n e d at a c o n s t a n t t e m p e r a t u r e o f 21°C a n d r a t chow a n d w a t e r w e r e a v a i l a b l e ad l i b i t u m . For three days prior to d r u g a d m i n i s t r a t i o n t h e s u b j e c t s w e r e bro-u--ght----~ t h e e x p e r i m e n t a l room, h a n d l e d , g i v e n s . c . s a l i n e i n j e c t i o n s a n d p l a c e d i n t o a h o l d i n g c a g e in o r d e r to h a b i t u a t e them to t h e e x p e r i m e n t a l p r o c e d u r e a n d t h e r e b y r e d u c e t h e s t r e s s r e s p o n s e to h a n d l i n g ( 2 5 ) . B u p r e n o r p h i n e h y d r o c h l o r i d e was o b t a i n e d from t h e N a t i o n a l I n s t i t u t e on D r u g A b u s e , m o r p h i n e s u l f a t e p e n t a h y d r a t e was o b t a i n e d from M a l l i n c k r o d t I n c . ( S t . L o u i s , MO) a n d e t h y l k e t o e y c l a z o c i n e m e t h a n e s u l f o n a t e was a g i f t of S t e r l i n g - W i n t h r o p R e s e a r c h I n s t i t u t e ( R e n s s e l a e r , New Y o r k ) . The drugs were i n i t i a l l y d i s s o l v e d in 8.5% l a c t i c a c i d . A small amount o f 0.9% s a l i n e was a d d e d followed b y t h e a d d i t i o n o f 0.1 N NaOH to r a i s e t h e p H . T h e MS a n d EKC s o l u t i o n s w e r e b r o u g h t to volume b y t h e a d d i t i o n o f 0.9% s a l i n e a n d t h e BUP solution by the addition of distilled water. This solution procedure did not c a u s e b r e a k d o w n of t h e c o m p o u n d s ( 2 0 ) . All s o l u t i o n s u s e d w i t h i n an e x p e r i ment w e r e a d j u s t e d to t h e same pH ( 3 . 8 - 4 . 0 ) . T h e v e h i c l e c o n t r o l was t h e s o l u t i o n u s e d to d i s s o l v e t h e s o l u t i o n s u n d e r s t u d y . All e x p e r i m e n t s w e r e p e r f o r m e d b e t w e e n 0900 a n d 1100 h . On t h e d a y o f d r u g a d m i n i s t r a t i o n t h e r a t s w e r e r e m o v e d from t h e home c a g e , w e i g h e d , i n j e c t e d s . c . b e h i n d t h e n e c k with e i t h e r d r u g o r t h e v e h i c l e c o n t r o l and plaeed into a holding cage. T h e i n j e c t i o n volume was 1.0 m l / k g o f b o d y weight. 30 m i n u t e s a f t e r t h e i n j e c t i o n t h e r a t s w e r e b r i e f l y e x a m i n e d f o r
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g r o s s b e h a v i o r a l c h a n g e s s u c h a s c a t a t o n i a a n d r i g i d i t y (26) a n d t h e i r t a i l s pinched as a rough measure of analgesia. I m m e d i a t e l y following t h e b e h a v i o r a l examination the rats were sacrificed by decapitation and trunk blood collected. T h e s a m p l e s w e r e s t o r e d at 4°C u n t i l t h e b l o o d c l o t t e d . Following centrifug a t i o n t h e s e r u m was a l i q u o t e d i n t o v i a l s a n d s t o r e d at - 2 0 ° C . T h e r e l e a s e o f ACTH was i n d i r e c t l y d e t e r m i n e d b y m e a s u r i n g t h e s e r u m l e v e l s of c o r t i c o s t e r o n e . C o r t i c o s t e r o n e , GH, PRL, LH a n d TSH w e r e measured by radioimmunoassay as previously described (27,28). All s a m p l e s from a g i v e n e x p e r i m e n t w e r e r u n w i t h i n t h e same a s s a y . T h e f r e q u e n c y d i s t r i b u t i o n s o f t h e s e r u m l e v e l s o f h o r m o n e s in c o n t r o l s u b j e c t s w e r e f o u n d to d e p a r t from n o r m a l i t y a s p r e v i o u s l y d e s c r i b e d (29). A n a l y s i s of t h e d a t a also r e v e a l e d h e t e r o g e n e i t y of v a r i a n c e . Computer p o w e r f u n c t i o n a n a l y s i s r e v e a l e d no s y s t e m a t i c r e l a t i o n s h i p b e t w e e n t h e m e a n s and the standard deviations making transformations of the raw data inappropriate (30). Therefore, nonparametric statistical tests were utilized. T h e m u l t i p l e c o m p a r i s o n m e t h o d u s i n g r a n k sums g i v e n b y D u n n (31) was u s e d to t e s t f o r d i f f e r e n c e s b e t w e e n t h e c o n t r o l a n d d r u g g r o u p s . The experimentwise e r r o r r a t e (32) was u s e d a n d s e t at 0.05 f o r d e t e r m i n i n g s i g n i f i c a n t differences. Results T h e r e s u l t s a r e s h o w n in F i g u r e s 1 a n d 2. The administration of BUP d i d n o t i n d u c e s t a t i s t i c a l l y s i g n i f i c a n t c h a n g e s in t h e r e l e a s e o f c o r t i c o s t e r o n e o r LH. T h e r e was a t e n d e n c y f o r c o r t i c o s t e r o n e r e l e a s e to b e i n c r e a s e d following t h e l o w e r d o s e s b u t t h i s t e n d e n c y l e s s e n e d a s t h e d o s e increased. BUP c a u s e d a s i g n i f i c a n t i n c r e a s e in t h e s e r u m l e v e l s o f GH i n a dose dependent manner. In c o n t r a s t , s e r u m PRL s h o w e d a b i p h a s i c r e s p o n s e with t h e l o w e s t d o s e of BUP i n d u c i n g a s i g n i f i c a n t r i s e while t h e h i g h e s t d o s e caused a significant decrease. TSH r e l e a s e was i n h i b i t e d a f t e r all d o s e s o f MS w h e r e a s EKC a n d BUP e l i c i t e d a d i f f e r e n t p a t t e r n on TSH r e l e a s e c h a r a c t e r i z e d by deereases occurring only after the lower doses. All o f t h e s u b j e c t s r e c e i v i n g all d r u g s w e r e u n r e s p o n s i v e to a t a i l p i n c h a n d a p p e a r e d c a t a t o n i c . Discussion T h e p a t t e r n o f r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s f o l l o w i n g t h e s u b c u t a n e o u s a d m i n i s t r a t i o n of BUP at t h e 30 min s a m p l i n g p o i n t is c l e a r l y d i f f e r e n t from t h a t s e e n a f t e r t h e a d m i n i s t r a t i o n o f t h e mu a g o n i s t s . Morphine p r o d u c e s i n c r e a s e s in t h e r e l e a s e of c o r t i c o s t e r o n e GH, a n d PRL a n d d e c r e a s e s i n t h e r e l e a s e o f LH a n d TSH ( 1 3 , 1 5 , 1 6 , 2 0 ) . F o l l o w i n g t h e l o w e r d o s e s o f BUP t h e p a t t e r n r e s e m b l e s t h a t s e e n a f t e r MS e x c e p t n e i t h e r t h e r e l e a s e o f c o r t i c o s t e r o n e o r LH was a f f e c t e d . A f t e r t h e h i g h e s t d o s e o f BUP t h e r e l e a s e o f PRL was d e c r e a s e d ; a n e f f e c t t y p i c a l l y f o u n d a f t e r t h e a d m i n i s t r a t i o n o f opiate antagonists (17,18). H o w e v e r , at t h i s d o s e t h e r e l e a s e o f GH was s t i l l stimulated revealing typical opiate agonist activity. These differential findings i n d i c a t e t h a t t h e e f f e c t s of BUP c a n n o t b e e x p l a i n e d b y w a y o f i t s s i m p l y a c t i n g a s a m u a g o n i s t at low d o s e s a n d a m u a n t a g o n i s t at h i g h d o s e s . BUP d i d n o t c a u s e an i n c r e a s e i n t h e r e l e a s e o f c o r t i c o s t e r o n e . This is an u n u s u a l f i n d i n g with r e s p e c t to o p i a t e a g o n i s t s ( 1 3 ) . L a h t i a n d Collins (33) h a v e s u g g e s t e d t h a t t h e a b i l i t y o f an o p i a t e to i n d u c e d y s p h o r i a c a n b e p o s i t i v e l y c o r r e l a t e d with i t s c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y . This hypothesis f i t s with t h e p r e s e n t d a t a s i n c e BUP h a s n o t b e e n r e p o r t e d to c a u s e d y s p h o r i a in h u m a n s ( 5 , 9 ) . In c o n t r a s t to t h e l a c k of c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y , BUP was a p o t e n t r e l e a s e r o f GH. T h e p a t t e r n o f r e l e a s e o f GH f o l l o w i n g MS a n d EKC h a v e b e e n r e p o r t e d to b e d i f f e r e n t in t h a t EKC e l i c i t s a d o s e
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VEHICLE
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13.1
DOSE BUPRENORpHINE (JJMOLES/K6)
FIG. 1 The effects of the s . c . a d m i n i s t r a t i o n o f BUP on t h e s e r u m l e v e l s o f e o r t i c o s t e r o n e , GH, PRL, LH a n d T S H . O r d i n a t e : m e d i a n s e r u m l e v e l s in ng/ml. Abscissa: d o s e o f BUP in lamoles/kg ( 0 . 1 3 , 1.32 an d 6.60 m g / k g ) . N=7-11. * S i g n i f i c a n t l y (p < 0.05) d i f f e r e n t from v e h i c l e c o n t r o l .
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The e f f e c t s of the s . c . a d m i n i s t r a t i o n of MS and EKC on the serum levels of TSH. O r d i n a t e : median serum levels of TSH in ng/m]. A b s c i s s a : dose of MS a n d EKC in umoles b a s e / k g (5, 10, 20 a n d 5.18, 10.36, 20.72 m g / k g r e s p e c t i v e l y ) . N = 8. * S i g n i f i c a n t l y (p < 0.05) d i f f e r e n t from vehicle c o n t r o l .
d e p e n d e n t r i s e in GH (20) while t h e r e l e a s e of GH following high doses of MS is l e s s t h a n a f t e r lower doses ( 2 0 , 2 5 , 3 4 ) . T h e r e f o r e , t h e p a t t e r n of GH r e l e a s e following BUP is more EKC-like t h a n MS-like. Since s t r e s s c a u s e s a d e c r e a s e in serum GH levels ( 2 9 , 3 5 , 3 6 ) , one h y p o t h e s i s for t h e GH p a t t e r n seen a f t e r MS is t h a t the h i g h e r doses of MS a r e s t r e s s f u l to r a t s (20). If t h e failure of BUP to effect c o r t i c o s t e r o n e r e l e a s e is i n d i c a t i v e t h a t BUP does not i n d u e s s t r e s s , t h e n t h i s could account for the d o s e - d e p e n d e n t r a t h e r t h a n U - s h a p e d p a t t e r n of GH r e l e a s e . An a l t e r n a t i v e h y p o t h e s i s is t h a t BUP and EKC r e l e a s e GH via a d i f f e r e n t r e c e p t o r t h a n the M S - i n d u c e d r e l e a s e . With r e s p e c t to EKC, e v i d e n c e in s u p p o r t of t h i s h y p o t h e s i s is the f i n d i n g t h a t t h e E K C - i n d u c e d r e l e a s e of GH is a n t a g o n i z e d b y p r e t r e a t m e n t with WIN 44,441-3 while t h e M S - i n d u c e d r i s e is u n a f f e c t e d (21). With r e s p e c t to PRL r e l e a s e , BUP c l e a r l y r e v e a l e d a p a t t e r n i n d i c a t i n g a g o n i s t a c t i v i t y following the lowest dose a n d a n t a g o n i s t a c t i v i t y a f t e r the h i g h e s t d o s e . The p a t t e r n of PRL r e l e a s e is m a r k e d l y d i f f e r e n t from t h e p a t t e r n of GH r e l e a s e where a monotonic d o s e - r e s p o n s e r e l a t i o n s h i p is s e e n . One p o s s i b l e e x p l a n a t i o n is t h a t GH and PRL a r e r e l e a s e d b y d i f f e r e n t opiate receptor subtypes (20,21,37,38). S t u d i e s have d e m o n s t r a t e d antagonism of mu r e c e p t o r s b y EKC ( 3 9 , 4 0 , 4 1 ) , and opiate a n t a g o n i s t s such as naloxone cause a fall in serum PRL when given alone (17,18). Wood et 8]. (42) h a v e r e p o r t e d t h a t mixed a g o n i s t - a n t a g o n i s t s p r o d u c e b i p h a s i c c h a ~ e - s in s t r i a t a l dopamine metabolism. Since the r e l e a s e of PRL is t h o u g h t to be u n d e r t h e c o n t r o l of a PRL r e l e a s e i n h i b i t o r y f a c t o r which has b e e n s u g g e s t e d to be dopamine ( 4 3 , 4 4 ) , t h e b i p h a s i e e f f e c t s on s t r i a t a l dopamine metabolism i n d u c e d b y mixed mu a g o n i s t - a n t a g o n i s t s could e x p l a i n t h e i r b i p h a s i e e f f e c t s on PRL r e l e a s e if t h e c h a n g e s in s t r i a t a l dopamine metabolism r e f l e c t a similar phenomenon in t h e t u b e r o i n f u n d i b u l a r d o p a m i n e r g i c s y s t e m . T h e r e f o r e BUP and EKC may r e l e a s e PRL due to t h e i r a c t i v i t y as mixed mu a g o n i s t - a n t a g o n i s t s while GH is r e l e a s e d
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via kappa receptor i n t e r a c t i o n s . T h e e f f e c t s of BUP on t h e r e l e a s e of TSH s h o w e d an i n i t i a l a g o n i s t a c t i v i t y with t h e h i g h e s t dose r e v e a l i n g a n t a g o n i s t a c t i v i t y t h a t b l o c k e d t h e f i r s t effect ( 4 5 ) . T h e a d m i n i s t r a t i o n of EKC showed a s i m i l a r b i p h a s i c p a t t e r n of TSH r e l e a s e , a p a t t e r n ~ o n s i s t e n t with mixed mu agonist-antagonist activity. No c h a n g e s i n s e r u m LH l e v e l s were s e e n a f t e r BUP. F a i l u r e to see e v i d e n c e of a g o n i s t a c t i v i t y with r e s p e c t to LH r e l e a s e i n h i b i t i o n could be d u e to t h e time p o i n t of s e r u m s a m p l i n g ; a l a t e r time p o i n t c o u l d h a v e s h o w n a t y p i c a l opiate a g o n i s t - i n d u c e d fall ( 1 5 ) . H o w e v e r , BUP does n o t a p p e a r to act as a n o p i a t e a n t a g o n i s t with r e s p e c t to LH r e l e a s e s i n c e a n t a g o n i s t a c t i v i t y s h o u l d h a v e b e e n o b s e r v e d b y t h e 30 m i n u t e time p o i n t , a n i n t e r v a l w i t h i n which o t h e r o p i a t e a n t a g o n i s t s elicit a d r a m a t i c r i s e i n LH ( 1 6 , 2 1 ) . M e n d e l s o n et al. (46) h a v e r e p o r t e d t h a t c h r o n i c BUP c a u s e s e l e v a t e d l e v e l s of PRL a n d d e c r e a s e d l e v e l s of LH i n male h e r o i n a d d i c t s . It is n o t c l e a r i f t h e d i f f e r e n c e s b e t w e e n t h e i r r e s u l t s a n d t h e r e s u l t s of t h e p r e s e n t s t u d y a r e d u e to s p e c i e s d i f f e r e n c e s , r e l a t i v e dose d i f f e r e n c e o r t h e e f f e c t s of c h r o n i c v e r s u s a c u t e d r u g a d m i n i s t r a t i o n . It is i n t e r e s t i n g to n o t e t h a t in t h e i r s t u d y t o l e r a n c e d i d n o t d e v e l o p to t h e PRL a n d LH e f f e c t s . M e n d e l s o n et al. (47) also r e p o r t e d t h a t t h e e f f e c t s of BUP on p l a s m a PRL a n d LH l e v e l s were much s m a l l e r t h a n t h o s e o b s e r v e d with o t h e r less p o t e n t o p i a t e a g o n i s t s ; f i n d i n g s c o n s i s t e n t with t h e p r e s e n t s t u d y . B r o w n et al. (47) r e p o r t e d o n l y a fall i n PRL a f t e r BUP i n t h e r a t b u t t h e y m e a s u - ~ d - - P R L 60 m i n u t e s a f t e r d r u g a d m i n i s t r a t i o n i n c o n t r a s t to 30 m i n u t e s i n t h e p r e s e n t study. I n s u m m a r y , BUP d i f f e r e n t i a l l y a f f e c t s t h e r e l e a s e of c o r t i c o s t e r o n e , GH, PRL, LH a n d TSH. It a p p e a r s to act as a mixed a g o n i s t - a n t a g o n i s t with r e s p e c t to PRL a n d TSH r e l e a s e , a full a g o n i s t with r e s p e c t to GH r e l e a s e , while t h e i n t e r a c t i o n s with r e s p e c t to c o r t i c o s t e r o n e a n d LH r e l e a s e a r e l e s s clear. T h i s is f u r t h e r e v i d e n c e for t h e i n v o l v e m e n t of d i f f e r e n t r e c e p t o r s in m e d i a t i n g o p i a t e - i n d u c e d c h a n g e s i n t h e r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s . T h e d a t a i n d i c a t e t h e u t i l i t y of s t u d y i n g p a t t e r n s of h o r m o n e r e l e a s e as well as t h e n e c e s s i t y of e x a m i n i n g a wide dose r a n g e of d r u g for c h a r a c t e r i z i n g a n d d e f i n i n g opiate a g o n i s t s a n d a g o n i s t - a n t a g o n i s t s . Acknowledgement We t h a n k Ms. K a r e n R o b e r t s for a s s i s t a n c e i n t h e p r e p a r a t i o n of t h i s manuscript. T h i s work was s u p p o r t e d b y a National I n s t i t u t e of D r u g A b u s e G r a n t DA-01006. RNP was t h e r e c i p i e n t of a National I n s t i t u t e of G e n e r a l Medical S c i e n c e s p r e d o e t o r a l t r a i n e e s h i p 7304 a n d a NRSA p r e d o c t o r a l t r a i n e e s h i p MH-15345-03. References i. 2. 3. 4. 5. 6. 7.
W.R. MARTIN, C . G . EADES, J . A . THOMPSON, R . E . HUPPLER a n d P . E . GILBERT, J . P h a r m a c o l . E x p . T h e r . 197, 517-532 (1976). A. COWAN, J.W. LEWIS a n d I . R . MACFARLANE, B r . J. P h a r m . 60, 537-545 (1977). J . J . C . JACOB a n d K. RAMABADRAN, B r . J. P h a r m a c . 64, 91-98 (1978). J . E . DUM a n d A. HERZ, B r . J . P h a r m a c . 74, 627-633 (i-~J-S1). D.R. JASINSKI, J . S . PEVNICK a n d J . D . GRIFFITH, Arch. Gen. P s y c h i a t r y 35, 601-616 (1978). T . YANAGI~A, S. KATOH, Y. YAKASA a n d N. OINUMA, NIDA R e s e a r c h M o n o g r a p h 41, 208-214 (1982). J . E . D U M , - ~ . BLASIG a n d A. HERZ, E u r . J. P h a r m a c o l . 70, 293-300
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M.G.C. GILLAN, H.W. KOSTERLITZ and J. MAGNAN, Brit. J. Pharmac. 72, 13-15 (1981). P--~L. WOOD, J.W. RICHARD and M. THAKUR, Life Sci. 31, 2313-2317 (1982). P.L. WOOD, D. SANSCHAGRIN, J.W. RICHARD and M. THUKAR, J. Pharm. Ex. Ther. 226, 545-550 (1983). P.L. WOOD, M. g~'-OTLAND, J . W . RICHARD and A. RACKHAM, J. Pharmacol. Exp. Ther. 215, 697-703 (1980). E. DEL POZO and E. FLUCKIGER, Clinical Neuroendocrinology: A Pathophysiolo~ieal Approach, G. Tolls, F. Labrie, J.B. Martin and F. Naftolin, eds., pp. 429-435, Raven Press, New York (1979). G . R . VAN LOON and G.M. BROWN, Systemic Endocrinology, 2nd Ed., C. Ezrin, J.O. Godden and R. Volpe, eds., pp. 20-44, Harper and Row, New York (1979). S. KARETI, J.E. MORETON and J. KHAZAN, Neuropharmacology 19, 195-201 (1980). J.H. MENDELSON, J. ELLINGBOE, N . K . MELLO and J. KUEHNLE, J. Pharmacol. Exp. Ther. 220, 252-255 (1982). B. BROWN, P.W. DETT--~R, P.R. DOBSON, A.G. LYNN, G. METCALF and B.A. MORGAN, J. Pharm. Pharmacol. 30, 644-645 (1978).
Pergamon Press
THE EFFECTS OF THE ACUTE ADMINISTRATION OF BUPRENORPHINE HYDROCHLORIDE ON THE RELEASE OF ANTERIOR PITUITARY HORMONES IN THE RAT: EVIDENCE FOR THE INVOLVEMENT OF MULTIPLE OPIATE RECEPTORS Robert N. Pechnick l, Robert George 2 and Russell E. Poland Department of Pharmaeology School of Medicine, the Brain Research Institute and the L a b o r a t o r y of Neuroendoerinology University of California Los Angeles, CA 90024 and Division of Biological P s y c h i a t r y Harbor-UCLA Medical Center Torrance, California 90502 (Received in final form August 29~ 1985)
Summary Multiple opiate r e c e p t o r agonists and antagonists have been found to p r o d u c e different p a t t e r n s of anterior p i t u i t a r y hormone release. The p r e s e n t studies examined the p a t t e r n of anterior p i t u i t a r y hormone release p r o d u c e d b y b u p r e n o r p h i n e . The effects of the kappa agonist ethylketoeyclazoeine on t h y r o i d stimulating hormone release were also examined. Following b u p r e n o r p h i n e , serum levels of corticosterone and luteinizing hormone were not changed while growth hormone release was stimulated in a d o s e - d e p e n d e n t manner. Prolactin release was stimulated after the lowest dose of b u p r e norphine while the highest dose induced a fall in serum prolactin. Similar biphasic effects on t h y r o i d stimulating hormone were seen after either b u p r e n o r p h i n e or ethylketocyclazocine. The results provide s u p p o r t for the role of multiple opiate r e c e p t o r s in opiateinduced changes in anterior pituitary hormone release. B u p r e n o r p h i n e (BUP) is an opiate alkaloid with both agonist and antagonist activity that was classified in the dog as a partial mu agonist b y Martin et al. (1). In rodent antinocieeptive assays BUP is 25 - 40 times more potent than morphine following subcutaneous injection (2). However, the d o s e - r e s p o n s e relationship of BUP with r e s p e c t to analgesia has been found to be bell-shaped with the antinociceptive activity d e c r e a s i n g at h i g h e r doses after initial d o s e - d e p e n d e n t increases ( 2 , 3 , 4 ) . BUP also has significant opiate antagonist activity in that it can antagonize the analgesic activity of morphine as well as precipitate withdrawal in morphine-dependent subjects ( 2 , 5 , 6 ) . As with o t h e r opiate agonists, tolerance develops upon repeated administration ( 2 , 4 , 6 ) , however, little or no abstinence syndrome is seen following narcotic Ipresent address: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, School of Medicine, University of California, Los Angeles, California 90024. ~to whom r e p r i n t r e q u e s t s should be a d d r e s s e d . 0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.
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a n t a g o n i s t c h a l l e n g e o r a b r u p t w i t h d r a w a l in r a t s ( 7 ) , m o n k e y s ( 2 , 6 ) a n d man (5,8). In f u r t h e r c o n t r a s t to o t h e r m i x e d a g o n i s t - a n t a g o n i s t s BUP d o e s n o t p r o d u c e d y s p h o r i a (2) a n d h a s b e e n r e p o r t e d to p r o d u c e p o s i t i v e s u b j e c t i v e e f f e c t s a n d e u p h o r i a in h e r o i n a d d i c t s ( 5 , 9 ) . The unique pattern of activity o f BUP a l o n g with i t s low d e g r e e of t o x i c i t y ( i 0 ) h a s l e d to i t s s u g g e s t e d clinical use as an analgesic (ll), a s an a n t i d e p r e s s a n t ( 1 2 ) , a n d in t h e p h a r m a c o t h e r a p y of h e r o i n a d d i c t i o n ( 9 ) . T h e e f f e c t s o f t h e a d m i n i s t r a t i o n o f o p i a t e s on t h e r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s h a v e b e e n e x t e n s i v e l y s t u d i e d in t h e r a t ( 1 3 , 1 4 , 1 5 , 1 6 ) . T h e a c u t e a d m i n i s t r a t i o n o f mu o p i a t e a g o n i s t s c a u s e s i n c r e a s e s in t h e r e l e a s e o f A C T H , g r o w t h h o r m o n e ( G H ) , p r o l a c t i n ( P R L ) a n d d e c r e a s e s in l u t e i n i z i n g h o r m o n e (LH) a n d t h y r o i d s t i m u l a t i n g h o r m o n e ( T S H ) . When a d m i n i s t e r e d alone opiate antagonists produce a different pattern of release characterized by a fall in PRL a n d a r i s e in LH p r e s u m a b l y v i a t h e i n h i b i t i o n o f e n d o g e n o u s o p i o i d p e p t i d e s t h a t t o n i c a l l y c o n t r o l t h e r e l e a s e of t h e s e h o r m o n e s ( 1 7 , 1 8 , 1 9 ) . It h a s r e c e n t l y b e e n s h o w n t h a t t h e a d m i n i s t r a t i o n o f t h e p r o t o t y p e k a p p a o p i a t e a g o n i s t [ a s d e f i n e d b y M a r t i n et al. ( 1 ) ] e t h y l k e t o c y c l a z o c i n e (EKC) e l i c i t s a d i f f e r e n t p a t t e r n of r e l e a s e from t h a t s e e n following t h e a d m i n i s t r a t i o n o f t h e mu a g o n i s t m o r p h i n e ( 2 0 , 2 1 ) . It is o f i n t e r e s t to c h a r a c t e r i z e t h e p a t t e r n of a n t e r i o r p i t u i t a r y h o r m o n e r e l e a s e i n d u c e d b y BUP s i n c e BUP h a s b o t h mu a g o n i s t a n d a n t a g o n i s t a c t i v i t y a n d also s h o w s a c t i v i t y s u g g e s t i n g t h e involvement of kappa receptors (22,23,24). The comparison of the pattern of r e l e a s e s e e n a f t e r BUP a d m i n i s t r a t i o n with t h e p a t t e r n s seen after the a d m i n i s t r a t i o n o f mu a g o n i s t s , mu a n t a g o n i s t s a n d k a p p a a g o n i s t s p r o v i d e s an i n d i e a t i o n a s to how BUP is i n t e r a c t i n g with o p i a t e r e c e p t o r s . The purpose of t h i s s t u d y is to c h a r a c t e r i z e t h e p a t t e r n o f a n t e r i o r p i t u i t a r y h o r m o n e r e l e a s e i n d u c e d b y t h e a c u t e a d m i n i s t r a t i o n of BUP. T h e e f f e c t s of t h e a d m i n i s t r a t i o n o f m o r p h i n e s u l f a t e (MS) a n d EKC on t h e r e l e a s e of TSH will also b e d e s c r i b e d a n d c o m p a r e d with t h e r e s u l t s s e e n f o l l o w i n g t h e a d m i n i s t r a t i o n of BUP. Materials and Methods Male, S p r a g u e - D a w l e y r a t s (280-300 g) w e r e h o u s e d 6 p e r c a g e u n d e r a 12 h l i g h t - d a r k c y c l e ( l i g h t s on 0700-1900 h ) f o r 7 d a y s p r i o r to d r u g administration. T h e h o u s i n g r o o m was m a i n t a i n e d at a c o n s t a n t t e m p e r a t u r e o f 21°C a n d r a t chow a n d w a t e r w e r e a v a i l a b l e ad l i b i t u m . For three days prior to d r u g a d m i n i s t r a t i o n t h e s u b j e c t s w e r e bro-u--ght----~ t h e e x p e r i m e n t a l room, h a n d l e d , g i v e n s . c . s a l i n e i n j e c t i o n s a n d p l a c e d i n t o a h o l d i n g c a g e in o r d e r to h a b i t u a t e them to t h e e x p e r i m e n t a l p r o c e d u r e a n d t h e r e b y r e d u c e t h e s t r e s s r e s p o n s e to h a n d l i n g ( 2 5 ) . B u p r e n o r p h i n e h y d r o c h l o r i d e was o b t a i n e d from t h e N a t i o n a l I n s t i t u t e on D r u g A b u s e , m o r p h i n e s u l f a t e p e n t a h y d r a t e was o b t a i n e d from M a l l i n c k r o d t I n c . ( S t . L o u i s , MO) a n d e t h y l k e t o e y c l a z o c i n e m e t h a n e s u l f o n a t e was a g i f t of S t e r l i n g - W i n t h r o p R e s e a r c h I n s t i t u t e ( R e n s s e l a e r , New Y o r k ) . The drugs were i n i t i a l l y d i s s o l v e d in 8.5% l a c t i c a c i d . A small amount o f 0.9% s a l i n e was a d d e d followed b y t h e a d d i t i o n o f 0.1 N NaOH to r a i s e t h e p H . T h e MS a n d EKC s o l u t i o n s w e r e b r o u g h t to volume b y t h e a d d i t i o n o f 0.9% s a l i n e a n d t h e BUP solution by the addition of distilled water. This solution procedure did not c a u s e b r e a k d o w n of t h e c o m p o u n d s ( 2 0 ) . All s o l u t i o n s u s e d w i t h i n an e x p e r i ment w e r e a d j u s t e d to t h e same pH ( 3 . 8 - 4 . 0 ) . T h e v e h i c l e c o n t r o l was t h e s o l u t i o n u s e d to d i s s o l v e t h e s o l u t i o n s u n d e r s t u d y . All e x p e r i m e n t s w e r e p e r f o r m e d b e t w e e n 0900 a n d 1100 h . On t h e d a y o f d r u g a d m i n i s t r a t i o n t h e r a t s w e r e r e m o v e d from t h e home c a g e , w e i g h e d , i n j e c t e d s . c . b e h i n d t h e n e c k with e i t h e r d r u g o r t h e v e h i c l e c o n t r o l and plaeed into a holding cage. T h e i n j e c t i o n volume was 1.0 m l / k g o f b o d y weight. 30 m i n u t e s a f t e r t h e i n j e c t i o n t h e r a t s w e r e b r i e f l y e x a m i n e d f o r
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g r o s s b e h a v i o r a l c h a n g e s s u c h a s c a t a t o n i a a n d r i g i d i t y (26) a n d t h e i r t a i l s pinched as a rough measure of analgesia. I m m e d i a t e l y following t h e b e h a v i o r a l examination the rats were sacrificed by decapitation and trunk blood collected. T h e s a m p l e s w e r e s t o r e d at 4°C u n t i l t h e b l o o d c l o t t e d . Following centrifug a t i o n t h e s e r u m was a l i q u o t e d i n t o v i a l s a n d s t o r e d at - 2 0 ° C . T h e r e l e a s e o f ACTH was i n d i r e c t l y d e t e r m i n e d b y m e a s u r i n g t h e s e r u m l e v e l s of c o r t i c o s t e r o n e . C o r t i c o s t e r o n e , GH, PRL, LH a n d TSH w e r e measured by radioimmunoassay as previously described (27,28). All s a m p l e s from a g i v e n e x p e r i m e n t w e r e r u n w i t h i n t h e same a s s a y . T h e f r e q u e n c y d i s t r i b u t i o n s o f t h e s e r u m l e v e l s o f h o r m o n e s in c o n t r o l s u b j e c t s w e r e f o u n d to d e p a r t from n o r m a l i t y a s p r e v i o u s l y d e s c r i b e d (29). A n a l y s i s of t h e d a t a also r e v e a l e d h e t e r o g e n e i t y of v a r i a n c e . Computer p o w e r f u n c t i o n a n a l y s i s r e v e a l e d no s y s t e m a t i c r e l a t i o n s h i p b e t w e e n t h e m e a n s and the standard deviations making transformations of the raw data inappropriate (30). Therefore, nonparametric statistical tests were utilized. T h e m u l t i p l e c o m p a r i s o n m e t h o d u s i n g r a n k sums g i v e n b y D u n n (31) was u s e d to t e s t f o r d i f f e r e n c e s b e t w e e n t h e c o n t r o l a n d d r u g g r o u p s . The experimentwise e r r o r r a t e (32) was u s e d a n d s e t at 0.05 f o r d e t e r m i n i n g s i g n i f i c a n t differences. Results T h e r e s u l t s a r e s h o w n in F i g u r e s 1 a n d 2. The administration of BUP d i d n o t i n d u c e s t a t i s t i c a l l y s i g n i f i c a n t c h a n g e s in t h e r e l e a s e o f c o r t i c o s t e r o n e o r LH. T h e r e was a t e n d e n c y f o r c o r t i c o s t e r o n e r e l e a s e to b e i n c r e a s e d following t h e l o w e r d o s e s b u t t h i s t e n d e n c y l e s s e n e d a s t h e d o s e increased. BUP c a u s e d a s i g n i f i c a n t i n c r e a s e in t h e s e r u m l e v e l s o f GH i n a dose dependent manner. In c o n t r a s t , s e r u m PRL s h o w e d a b i p h a s i c r e s p o n s e with t h e l o w e s t d o s e of BUP i n d u c i n g a s i g n i f i c a n t r i s e while t h e h i g h e s t d o s e caused a significant decrease. TSH r e l e a s e was i n h i b i t e d a f t e r all d o s e s o f MS w h e r e a s EKC a n d BUP e l i c i t e d a d i f f e r e n t p a t t e r n on TSH r e l e a s e c h a r a c t e r i z e d by deereases occurring only after the lower doses. All o f t h e s u b j e c t s r e c e i v i n g all d r u g s w e r e u n r e s p o n s i v e to a t a i l p i n c h a n d a p p e a r e d c a t a t o n i c . Discussion T h e p a t t e r n o f r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s f o l l o w i n g t h e s u b c u t a n e o u s a d m i n i s t r a t i o n of BUP at t h e 30 min s a m p l i n g p o i n t is c l e a r l y d i f f e r e n t from t h a t s e e n a f t e r t h e a d m i n i s t r a t i o n o f t h e mu a g o n i s t s . Morphine p r o d u c e s i n c r e a s e s in t h e r e l e a s e of c o r t i c o s t e r o n e GH, a n d PRL a n d d e c r e a s e s i n t h e r e l e a s e o f LH a n d TSH ( 1 3 , 1 5 , 1 6 , 2 0 ) . F o l l o w i n g t h e l o w e r d o s e s o f BUP t h e p a t t e r n r e s e m b l e s t h a t s e e n a f t e r MS e x c e p t n e i t h e r t h e r e l e a s e o f c o r t i c o s t e r o n e o r LH was a f f e c t e d . A f t e r t h e h i g h e s t d o s e o f BUP t h e r e l e a s e o f PRL was d e c r e a s e d ; a n e f f e c t t y p i c a l l y f o u n d a f t e r t h e a d m i n i s t r a t i o n o f opiate antagonists (17,18). H o w e v e r , at t h i s d o s e t h e r e l e a s e o f GH was s t i l l stimulated revealing typical opiate agonist activity. These differential findings i n d i c a t e t h a t t h e e f f e c t s of BUP c a n n o t b e e x p l a i n e d b y w a y o f i t s s i m p l y a c t i n g a s a m u a g o n i s t at low d o s e s a n d a m u a n t a g o n i s t at h i g h d o s e s . BUP d i d n o t c a u s e an i n c r e a s e i n t h e r e l e a s e o f c o r t i c o s t e r o n e . This is an u n u s u a l f i n d i n g with r e s p e c t to o p i a t e a g o n i s t s ( 1 3 ) . L a h t i a n d Collins (33) h a v e s u g g e s t e d t h a t t h e a b i l i t y o f an o p i a t e to i n d u c e d y s p h o r i a c a n b e p o s i t i v e l y c o r r e l a t e d with i t s c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y . This hypothesis f i t s with t h e p r e s e n t d a t a s i n c e BUP h a s n o t b e e n r e p o r t e d to c a u s e d y s p h o r i a in h u m a n s ( 5 , 9 ) . In c o n t r a s t to t h e l a c k of c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y , BUP was a p o t e n t r e l e a s e r o f GH. T h e p a t t e r n o f r e l e a s e o f GH f o l l o w i n g MS a n d EKC h a v e b e e n r e p o r t e d to b e d i f f e r e n t in t h a t EKC e l i c i t s a d o s e
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FIG. 1 The effects of the s . c . a d m i n i s t r a t i o n o f BUP on t h e s e r u m l e v e l s o f e o r t i c o s t e r o n e , GH, PRL, LH a n d T S H . O r d i n a t e : m e d i a n s e r u m l e v e l s in ng/ml. Abscissa: d o s e o f BUP in lamoles/kg ( 0 . 1 3 , 1.32 an d 6.60 m g / k g ) . N=7-11. * S i g n i f i c a n t l y (p < 0.05) d i f f e r e n t from v e h i c l e c o n t r o l .
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The e f f e c t s of the s . c . a d m i n i s t r a t i o n of MS and EKC on the serum levels of TSH. O r d i n a t e : median serum levels of TSH in ng/m]. A b s c i s s a : dose of MS a n d EKC in umoles b a s e / k g (5, 10, 20 a n d 5.18, 10.36, 20.72 m g / k g r e s p e c t i v e l y ) . N = 8. * S i g n i f i c a n t l y (p < 0.05) d i f f e r e n t from vehicle c o n t r o l .
d e p e n d e n t r i s e in GH (20) while t h e r e l e a s e of GH following high doses of MS is l e s s t h a n a f t e r lower doses ( 2 0 , 2 5 , 3 4 ) . T h e r e f o r e , t h e p a t t e r n of GH r e l e a s e following BUP is more EKC-like t h a n MS-like. Since s t r e s s c a u s e s a d e c r e a s e in serum GH levels ( 2 9 , 3 5 , 3 6 ) , one h y p o t h e s i s for t h e GH p a t t e r n seen a f t e r MS is t h a t the h i g h e r doses of MS a r e s t r e s s f u l to r a t s (20). If t h e failure of BUP to effect c o r t i c o s t e r o n e r e l e a s e is i n d i c a t i v e t h a t BUP does not i n d u e s s t r e s s , t h e n t h i s could account for the d o s e - d e p e n d e n t r a t h e r t h a n U - s h a p e d p a t t e r n of GH r e l e a s e . An a l t e r n a t i v e h y p o t h e s i s is t h a t BUP and EKC r e l e a s e GH via a d i f f e r e n t r e c e p t o r t h a n the M S - i n d u c e d r e l e a s e . With r e s p e c t to EKC, e v i d e n c e in s u p p o r t of t h i s h y p o t h e s i s is the f i n d i n g t h a t t h e E K C - i n d u c e d r e l e a s e of GH is a n t a g o n i z e d b y p r e t r e a t m e n t with WIN 44,441-3 while t h e M S - i n d u c e d r i s e is u n a f f e c t e d (21). With r e s p e c t to PRL r e l e a s e , BUP c l e a r l y r e v e a l e d a p a t t e r n i n d i c a t i n g a g o n i s t a c t i v i t y following the lowest dose a n d a n t a g o n i s t a c t i v i t y a f t e r the h i g h e s t d o s e . The p a t t e r n of PRL r e l e a s e is m a r k e d l y d i f f e r e n t from t h e p a t t e r n of GH r e l e a s e where a monotonic d o s e - r e s p o n s e r e l a t i o n s h i p is s e e n . One p o s s i b l e e x p l a n a t i o n is t h a t GH and PRL a r e r e l e a s e d b y d i f f e r e n t opiate receptor subtypes (20,21,37,38). S t u d i e s have d e m o n s t r a t e d antagonism of mu r e c e p t o r s b y EKC ( 3 9 , 4 0 , 4 1 ) , and opiate a n t a g o n i s t s such as naloxone cause a fall in serum PRL when given alone (17,18). Wood et 8]. (42) h a v e r e p o r t e d t h a t mixed a g o n i s t - a n t a g o n i s t s p r o d u c e b i p h a s i c c h a ~ e - s in s t r i a t a l dopamine metabolism. Since the r e l e a s e of PRL is t h o u g h t to be u n d e r t h e c o n t r o l of a PRL r e l e a s e i n h i b i t o r y f a c t o r which has b e e n s u g g e s t e d to be dopamine ( 4 3 , 4 4 ) , t h e b i p h a s i e e f f e c t s on s t r i a t a l dopamine metabolism i n d u c e d b y mixed mu a g o n i s t - a n t a g o n i s t s could e x p l a i n t h e i r b i p h a s i e e f f e c t s on PRL r e l e a s e if t h e c h a n g e s in s t r i a t a l dopamine metabolism r e f l e c t a similar phenomenon in t h e t u b e r o i n f u n d i b u l a r d o p a m i n e r g i c s y s t e m . T h e r e f o r e BUP and EKC may r e l e a s e PRL due to t h e i r a c t i v i t y as mixed mu a g o n i s t - a n t a g o n i s t s while GH is r e l e a s e d
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via kappa receptor i n t e r a c t i o n s . T h e e f f e c t s of BUP on t h e r e l e a s e of TSH s h o w e d an i n i t i a l a g o n i s t a c t i v i t y with t h e h i g h e s t dose r e v e a l i n g a n t a g o n i s t a c t i v i t y t h a t b l o c k e d t h e f i r s t effect ( 4 5 ) . T h e a d m i n i s t r a t i o n of EKC showed a s i m i l a r b i p h a s i c p a t t e r n of TSH r e l e a s e , a p a t t e r n ~ o n s i s t e n t with mixed mu agonist-antagonist activity. No c h a n g e s i n s e r u m LH l e v e l s were s e e n a f t e r BUP. F a i l u r e to see e v i d e n c e of a g o n i s t a c t i v i t y with r e s p e c t to LH r e l e a s e i n h i b i t i o n could be d u e to t h e time p o i n t of s e r u m s a m p l i n g ; a l a t e r time p o i n t c o u l d h a v e s h o w n a t y p i c a l opiate a g o n i s t - i n d u c e d fall ( 1 5 ) . H o w e v e r , BUP does n o t a p p e a r to act as a n o p i a t e a n t a g o n i s t with r e s p e c t to LH r e l e a s e s i n c e a n t a g o n i s t a c t i v i t y s h o u l d h a v e b e e n o b s e r v e d b y t h e 30 m i n u t e time p o i n t , a n i n t e r v a l w i t h i n which o t h e r o p i a t e a n t a g o n i s t s elicit a d r a m a t i c r i s e i n LH ( 1 6 , 2 1 ) . M e n d e l s o n et al. (46) h a v e r e p o r t e d t h a t c h r o n i c BUP c a u s e s e l e v a t e d l e v e l s of PRL a n d d e c r e a s e d l e v e l s of LH i n male h e r o i n a d d i c t s . It is n o t c l e a r i f t h e d i f f e r e n c e s b e t w e e n t h e i r r e s u l t s a n d t h e r e s u l t s of t h e p r e s e n t s t u d y a r e d u e to s p e c i e s d i f f e r e n c e s , r e l a t i v e dose d i f f e r e n c e o r t h e e f f e c t s of c h r o n i c v e r s u s a c u t e d r u g a d m i n i s t r a t i o n . It is i n t e r e s t i n g to n o t e t h a t in t h e i r s t u d y t o l e r a n c e d i d n o t d e v e l o p to t h e PRL a n d LH e f f e c t s . M e n d e l s o n et al. (47) also r e p o r t e d t h a t t h e e f f e c t s of BUP on p l a s m a PRL a n d LH l e v e l s were much s m a l l e r t h a n t h o s e o b s e r v e d with o t h e r less p o t e n t o p i a t e a g o n i s t s ; f i n d i n g s c o n s i s t e n t with t h e p r e s e n t s t u d y . B r o w n et al. (47) r e p o r t e d o n l y a fall i n PRL a f t e r BUP i n t h e r a t b u t t h e y m e a s u - ~ d - - P R L 60 m i n u t e s a f t e r d r u g a d m i n i s t r a t i o n i n c o n t r a s t to 30 m i n u t e s i n t h e p r e s e n t study. I n s u m m a r y , BUP d i f f e r e n t i a l l y a f f e c t s t h e r e l e a s e of c o r t i c o s t e r o n e , GH, PRL, LH a n d TSH. It a p p e a r s to act as a mixed a g o n i s t - a n t a g o n i s t with r e s p e c t to PRL a n d TSH r e l e a s e , a full a g o n i s t with r e s p e c t to GH r e l e a s e , while t h e i n t e r a c t i o n s with r e s p e c t to c o r t i c o s t e r o n e a n d LH r e l e a s e a r e l e s s clear. T h i s is f u r t h e r e v i d e n c e for t h e i n v o l v e m e n t of d i f f e r e n t r e c e p t o r s in m e d i a t i n g o p i a t e - i n d u c e d c h a n g e s i n t h e r e l e a s e of a n t e r i o r p i t u i t a r y h o r m o n e s . T h e d a t a i n d i c a t e t h e u t i l i t y of s t u d y i n g p a t t e r n s of h o r m o n e r e l e a s e as well as t h e n e c e s s i t y of e x a m i n i n g a wide dose r a n g e of d r u g for c h a r a c t e r i z i n g a n d d e f i n i n g opiate a g o n i s t s a n d a g o n i s t - a n t a g o n i s t s . Acknowledgement We t h a n k Ms. K a r e n R o b e r t s for a s s i s t a n c e i n t h e p r e p a r a t i o n of t h i s manuscript. T h i s work was s u p p o r t e d b y a National I n s t i t u t e of D r u g A b u s e G r a n t DA-01006. RNP was t h e r e c i p i e n t of a National I n s t i t u t e of G e n e r a l Medical S c i e n c e s p r e d o e t o r a l t r a i n e e s h i p 7304 a n d a NRSA p r e d o c t o r a l t r a i n e e s h i p MH-15345-03. References i. 2. 3. 4. 5. 6. 7.
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Buprenorphine and Pituitary Hormones
Vol. 37, No. 20, 1985
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