Effect of morphine and nalmefene on energy balance in diabetic and non-diabetic rats

PharmacologyBzochemtstry &Behavtor, Vol 29, pp 495-500 PergamonPress plc, 1988 Pnnted m the U S A

0091-3057/88 $3 00 + 00

Effect of Morphine and Nalmefene on Energy Balance in Diabetic and Non-Diabetic Rats A

S L E V I N E , I M. G R A C E , C. J. B I L L I N G T O N , B. A. G O S N E L L , D. D K R A H N , D. M. B R O W N A N D J. E. M O R L E Y

Neuroendocrme Research Laboratory, VA Medical Center and Departments o f Food Science and Nutrition Medicine and Laboratory Medtcme and Pathology, University o f Minnesota, St Paul-Mmneapohs, M N Department o f Physiology, University of Texas Health Science Center, Dallas, TX Department o f Psychiatry, University o f Michigan, Ann Arbor, MI and Geriatric Research, Education and Chmcal Center, VA Medical Center, Sepulveda, CA R e c e i v e d 4 J u n e 1987 LEVINE, A S , M GRACE, C J BILLINGTON, B A GOSNELL, D D KRAHN, D M BROWN AND J E MORLEY Effect of morphine and nalrnefene on energy balance m dtabetw and non-dtabetw rats PHARMACOL BIOCHEM BEHAV 29(3)495-500, 1988 --Male rats made dmbetlc by intravenous rejection of streptozotocm were used to evaluate the effect of the dmbetlc state on morphine- and nalmefene-mduced changes m food retake and body weight Morphme mcreased 4 hour food retake m non-dmbet~c rats after an initial rejection, but increased intake in diabetic rats only after repeated rejections Unhke short term measurements, morphine decreased food intake when measured over 24 or more hours in both groups Chronic rejection of morphine decreased body weight only m non-diabetic rats Feed efficiency data suggest that morphine had a more potent effect on energy balance m the non-dlabet~c rats The oplold antagomst, nalmefene, did not alter body weight in either group and only altered food intake m the diabetic animals These data are m concert w~th other reports indicating that the diabetic state renders animals less responsive to the effects of morphine on noocept~on and smooth muscle contraction Oplolds

Dmbetes

Morphine

Nalmefene

G L U C O S E has been shown to modulate the responsiveness of laboratory ammals to oplold effects In 1956 Davis et al [3] found that hypoglycemia potentiated the antlnoclceptlve action of morphine in rats as quantified by the tall flick method Simon et al [29,30] demonstrated that the analgesic effects of morphine, phenazoclne and levorphanol were decreased in rats made diabetic by injection of streptozotocln Pretreatment with hypertonlc dextrose or fructose produced the same effect [29,30] Shook et al [28] also reported that increasing the concentration of glucose in the media reduced the responsivlty of the electrically stimulated ileum to normorphine which suggests that glucose concentration, rather than insulin alteration, is the mediator of their m VlVO findings Recently, Shook and Dewey [27] found that diabetic mice were less physically dependent upon morphine than non-diabetic controls Genetically diabetic mice display Increased tall flick latencies to radiant heat relative to their httermate controls [9] Both diabetic patients and subjects refused with glucose had decreased pain thresholds and pmn tolerance [22]

1Requests for reprints should be addressed to Allen S Levlne, Ph Mmneapohs, MN 55417

Since it 1s known that glucose levels or glucose utlhzatlon can modulate feeding behavior, that opioids can stimulate food intake [7,21] and that glucose modulates oploid noclceptlve effects, ~t seems reasonable to believe that glucose might modulate oplold effects on food intake Our laboratory found that both genetically diabetic mice (C57 B L / K s - d b + / d b + ) and streptozotocln dtabetlc mice show enhanced sensitivity to naloxone-lnduced suppression of food intake [6] Rats made hypoglycemlc by injection of lnsuhn, a procedure that sttmulates food intake, are relatively insensitive to naloxone diminution of food intake [5,10], however, this may depend upon the environment in which the study IS conducted [25] In general, then, it appears that elevated glucose levels potentiate the naloxone effect, although we have found this to be markedly influenced by the animal's environment [8] Data concerning long term administration of oplold agonlsts and antagonists on food intake and body weight are few and confusing Chronic naltrexone infusions decreased food Intake in rats fed chow plus a 32% sucrose solution

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LEVINE ET AL

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better than m those ingesting only chow [16] Repeated lnjectmns of a zinc tannate preparatmn of naloxone decreased food retake only In rats receiving a high fat cafeteria diet [15] In a group of lean and obese Zucker rats, the long-acting oplold antagonist, nalmefene (6-desoxy-6 methylene naltrexone), decreased food intake but only slightly altered body weight [ll,12] On the other hand it has been reported that mice gain weight when g~ven naloxone and decrease their food retake after chromc morphine administration [26] In long term studies m humans naltrexone has been shown to shghtly decrease or have no effect on body weight [1,17] The effect of chromc admlmstratlon of oplolds and their antagonists on food mtake and body weight m dmbetlc vs non-dmbetlc rats Is not known In the present study we addressed this issue by injecting the oplold agonlst, morphine, and the oplold antagonist, nalmefene, in a group of streptozotocm-lnduced dmbet~c rats and non-dmbet~c rats of the same strain for a period of 24 days while measuring food intake and body weight Nalmefene is potent and long lived relative to naloxone and does not possess as much oplold agonlst activity as naloxone [4]

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METHOD

Male Sprague-Dawley rats were used for all studies and were housed under standard hghtlng and temperature conditions (12 hour/day artificml hght, 7 a m. to 7 p m , 25°C) Animals were gwen free access to Purina laboratory chow and to water At about 7 weeks of age rats were given an intravenous inJection (tad veto) of streptozotocln (55 mg/kg m 1 3% citric acid buffer, pH 4 5) followed by 2 ml of 30% dextrose Three weeks later they were bled vm the tail veto and glucose was measured using a Beckman Glucose Analyzer (Fullerton, CA) to assure a diabetic state (glucose=632+_22 mg/dl). Age-matched rats were used as non-diabetzc controls Food retake and body weight were quantified for 3 days before the start of the experimentation to acchmate the animals to handhng and daffy interruptions The rats were dlv]ded into five groups of ten and 1 group of eleven wh]ch allowed for three groups of dmbetlc and three groups of non-dmbetlc rats. To enable a balanced design for statistical analysis, one rat was omitted at random from the group containing eleven rats On day one of the study a single mject~on of either morphine sulfate (10 mg/kg, Eh Lilly and Co., Indmnapolls, IN), nalmefene (10 mg/kg, kindly prowded by Key Pharmaceuticals, I n c , Miami, FL) or vehicle was rejected subcutaneously Food retake was then measured at hours 1, 2, 4, 6 and 24. Durmg the ensuing 21 days, rats were reJected twice per day at about 0900 and 1600 hr On days 2 and 7 tood mtake was agam quantified at hours 1, 2, 4 and 6 (only 4 hour data are presented) Food retake and body weight were measured on days 3, 5, 10, 12, 15, 17, 19, and 22 Food intake was corrected for spdlage at each measurement and average dally intake was calculated by dividing the total food intake by the representative time period (eg grams eaten between (day 3/day 5)/3) Ammals were sacrificed on day 24 following one rejection of the appropriate drug and trunk bood was collected for analysis of glucose with a glucose ox~dase procedure (S~gma Chemical Co., St Lores, MO) All data are shown as mean+_SEM Data were analyzed by analys~s of variance (ANOVA) (repeated measures when appropriate). Post-hoc tests (least s~gmficant dtfference procedure-LSD) were only conducted ff the overall ANOVA demonstrated an interaction The error term for each posthoc test was calculated by a one factor ANOVA

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FIG 1 The effect of morphine (10 mg/kg bid) and nalmefene (10 mg/kg bid) on 4 hour food retake in diabetic (D) and non-dmbetlc (ND) rats on days 1, 2 and 7 of the study *p<0 05 compared to sahne controls for rats of same day and dmbetlc status

RESULTS

At sacrifice, trunk blood was sampled and serum was analyzed for glucose concentration Serum glucose levels in diabetic and non-diabetic animals were not altered following chronic injections of morphine or nalmefene (DlabeUc sahne=530_ + 14, morphine=496_2, nalmefene=511 +_8 mg/dl) (Non-Diabetic saline= 142_+3, morphine= 138+_2, nalmefene = 148_+5 mg/dl)

Short-Term Feedmg Studle~ The effect of morphine and nalmefene on food mtake m diabetic and non-diabetic control rats on day 1, day 2 and day 7 was analyzed by a 3-factor repeated measures ANOVA There were main effects of diabetic state, F(1,54)=11 72, of drug, F(2,54)--22 53, and of day of the study, F(2,108)=5 25 (all p ' s < 0 01) Also, there was a significant diabetic state x drug x day interaction Individual group comparisons (LSD procedure) mdlcated that morphine stimulated 4 hour food mtake in the non-diabetic rats on days 1, 2, and 7, whereas morphme only stimulated food intake in the dmbetlc rats on day 7 (F~g 1) Nalmefene had no significant effect on 4 hour food intake, although the mean Intakes after nalmefene were consistently less than control means Twenty-four hour food intake was s]gmficantly decreased m both d]abet]c and non-diabetic ammals following one injection (day 1) and following three reJections (day 1 + day 2) of morphine and nalmefene (Fig 2)

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FIG 3 The effect of chrome mjecUon of morphine (10 mg/kg b~d) and nalmefene (10 mg/kg bid) on average food retake in diabetic (D) and non-dmbetlc (ND) rats *p <0 05 compared to sahne controls for rats of same day and dmbetlc status 50 40 _q 4;

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FIG 2 Twenty-four hour food intake m diabetic and non-dmbeUc rats following morphine (l0 mg/kg bid) and nalmefene (10 mg/kg bid) rejections on days 1 and 2 of the study -tp<0 05 compared to sahne controls for rats of same day and dmbet~c status

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FIG 4 The effect of chronic injection of morphine (10 mg/kg) and nalmefene (10 mg/kg) on body weight in dmbetlc (D) and nondlabettc (ND) rats *p<0 05 compared to sahne controls for rats of same day and dmbet~c status

Chrontc Drug Studtes The effect of morphine and nalmefene on average food retake and on body weight change over 22 days was analyzed by a 3-factor repeated measures ANOVA There were mam effects of dmbetlc state, F(1,54)=846 93, of drug, F(2,54)= 9.34, and of day, F(7,378)=39 16 ( a l l p ' s < 0 001). There was a s]gmficant dmbeUc × drug mteractton, F(2,54)=5 22, p < 0 05, and a slgntficant dmbetlc × drug × day mteracUon, F(14,378)=2 86, p < 0 001 One factor ANOVA followed by LSD tests indicated that food retake was decreased by nalmefene and morphine m the dmbetlc rats, whereas only morphine decreased feeding at some time points m the nondmbetlc control rats (Fig. 3) Analysis of body weight data demonstrated main effects of diabetic state, F(1,54)=78 42, p < 0 001, and of day F(8,432)=63 85, p<0.001, but not of drug There was a slgmficant interaction of dtabeUc state × drug × day, F(16,432)=1.814, p<0.05. One factor ANOVA followed by the least slgnLfiCance d]fference test indicated that body weight was reduced due to morphine rejection only m the non-dmbetlc ammals (Fig. 4) Nalmefene failed to alter mean body weight m either group of rats Analysis of maxtmum percent body weight gain (maximum weight gaan or at least a negative weight change/initial body weight × 100) and maximum percent body weight loss (maximum weight loss or at least a negatwe weight change/initial body we~ght×100) substantmted the observaUon that morphine has a more potent effect in non-dmbet~c controls compared w~th diabetic rats (Fig. 5) In the non-dmbet~c rats the maximum percent body

weight lost by the rats treated with morphine was approximately 15%, in contrast to only above a 5% maximum body weight loss m the dmbet~c rats To integrate food retake and body weight data we calculated a "feed effioency ratio" (change m body weight [e]ther (+) weight gain or ( - ) weight loss] from day 0 dwlded by the cumulative amount of food eaten) Morphine decreased the feed efficiency ratio m dmbeUcs as well as non-dmbetlcs, but had a more potent effect in the non-dmbetlc group (drug × dmbeUc state lnteractmn F(2,54)=3 432,p<0.05 (Fig. 6) In contrast, nalmefene failed to alter the feed efficiency ratto In non-dmbetlcs, but did so m the dmbet~cs

DISCUSSION This study indicates that diabetic rats respond differently than non-dlabet~c control rats to the acute effects of morphine on food mtake as well as to the changes in food retake and body weight which occur followmg chrome morphine administration Morphine failed to stimulate short term food retake m diabetic animals following an lnmal exposure, whereas morphine stimulated feeding m non-dmbet]c controls rats after a single injection This might be secondary to the increased basal retake of food m the diabetics smce oplolds are less potent stimulators of feeding m a m m a l s chromcally food depraved [19] or during the nocturnal feedlng period [22]. However, repeated exposure of diabetic

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FIG 5 Maximum percent body weight loss (a) and percent body weight gain (b) in dmbetlc and non-diabetic rats following chromc injection of morphme (10 mg/kg bid) and nalmefene (10 mg/kg bid) tp<0 05 compared to sal,ne controls for rats of same day and dmbetlc status animals to morphine ultimately resulted in enhanced food intake We have previously reported this "reversetolerance" effect in normal ammals [22] Nalmefene faded to alter short term food consumption m either group of rats, probably due to a floor effect In contrast to the short term studies, chronic administration of morphine to both dmbetlc and non-diabetic rats resulted m decreased cumulative food intake Also, morphine resulted in a more marked decrease in body weight in the non-dmbetlc animals The feed efficiency ratios also substantiated the latter finding, suggesting that diabetic rats were somewhat resistant to morphine's effect on energy balance The above data are in concordance with those reported by Simon and his colleagues [29,30] They found that streptozotocln-mduced diabetic rats were less senslt~ve to the antlnooceptlve effects of morphine Recent data from the same laboratory indicates that hyperglycemia modifies the responses of guinea pig ileum and mouse vas deferens responses to normorphme [4.5] Prehmmary studies [31] indicate that glucose can enhance the bmdlng of naloxone to bram membranes It has also been shown that dmbetlc humans display decreased pare thresholds and pare tolerance [22] In general, tt appears that dmbetlc ammals respond differently to the effects of morphine on both pam and food intake when compared to non-diabetic control ammals Relatively few studies have examined the effect of chromc admlmstratlon of oplold agomsts or antagonists on food intake and body weight In our study the long-acting oplold antagonist, nalmefene, faded to alter body weight m either dmbetlc or non-diabetic rats Nalmefene did not decrease food intake m the non-dmbetic rats, but did decrease food intake shghtly in the diabetic rats McLaughhn and Bade [11] found that nalmefene decreased meal size and dally food intake, but increased meal frequency m Zucker rats and their lean httermates Body weight decreased dunng the first week of the study m the nalmefene treated animals compared with the sahne treated controls, however, subse-

quent weight gain was greater in the nalmefene treated rats The weight loss was more marked m the obese Zucker rats Thus, McLaughhn and Bade [11 ] found only slight effects of nalmefene on body weight Naltrexone, when given twice a day at 10 mg/kg to genetically obese (ob/ob) mice decreased the rate of weight gain in these obese mice but had no effect on their lean httermates [23] From the latter studies ~t seems that op~old antagonism seems to affect energy balance more readily in obese animals Similarly, It appears that oplold antagonism is more potent in animals fed palatable foods Repeated injections of a zinc tannate preparation of naloxone abolishes diet-reduced obesity m rats fed a high fat cafeteria diet, whereas no effect of oploid blockade was noted in rats fed a low fat diet [15] Chromc naltrexone infusions (200 p.g/kg/hr) decreased appetite more effectively m rats fed chow plus 32% sucrose compared to those fed chow alone [16] Brands et al [2] also found that a zinc tannate salt of naloxone only decreased food intake during the first few days of the study and body weight during the first ten days of the study Shimomura et al [26] reported that lean mice given dady morphine injections decreased food retake McLaughhn and Baile [ 1 2 ] reported that rats autolmmumzed against fl-endorphin increase both their food retake and body weight This suggests that chronically available endogenous fl-endorphm might result in a decrease m food retake and body weight Thls finding is m keeping with our previous study showing that peripherally infused beta-endorphm decreased food retake [18] The present study indicates that normal rats chromcally treated with morphine lose weight and ingest somewhat less food suggesting that morphine's effect on body weight could be due to increased energy expenditure, rather than secondary to its effects on feeding Also, nalmefene faded to decrease body weight in dmbetlc ammals, although food retake was decreased However. it is difficult to generahze these effects of morphine and/or fl-endorphm to all oplolds

MORPHINE, NALMEFENE

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499 The d e c r e a s e d f e e d efficiency n o t e d with c h r o n i c inJection o f m o r p h i n e s u g g e s t s an e f f e c t on e n e r g y c o n s e r v a t i o n M o r p h i n e s e e m s to h a v e d e c r e a s e d b o d y w e i g h t to a g r e a t e r e x t e n t t h a n can be a c c o u n t e d for by f o o d intake alone, particularly in the n o n - d m b e t l c animals C h r o n i c n a l o x o n e rej e c t i o n has b e e n r e p o r t e d by several i n v e s t i g a t o r s to i n c r e a s e o x y g e n c o n s u m p t i o n [14,15] H o w e v e r , M a r k s - K a u f m a n et al [16] f o u n d that although n a l t r e x o n e t r e a t m e n t a l t e r e d the r e s p i r a t o r y quotient, it had n o effect o n total o x y g e n cons u m p t i o n Oplolds are also k n o w n to affect hpld m e t a b o l i s m F o r e x a m p l e , R i c h t e r et al [24] d e m o n s t r a t e d that /3-11potropm stimulated h p o l y s l s in r a b b i t s T h u s , the p r e s e n t data indicate that m o r p h i n e , w h e n inj e c t e d c h r o m c a l l y , can alter b o d y w e i g h t The e f f e c t o f morp h i n e on b o d y weight is different in d m b e t i c animals w h e n c o m p a r e d to n o n - d i a b e t i c c o n t r o l s In general, diabetic animals a p p e a r to be less sensitive to the acute e f f e c t s o f m o r p h i n e on food intake and the e f f e c t s o f c h r o m c administration o f m o r p h i n e on b o d y weight

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These studies were supported, in part, by grants from the Veterans Admmlstrauon Medical Center. the National Institute of Drug Abuse (IROI-DA 03999-01) and the National Institutes of Health (DK-17697) We thank JoAnn Tallman for preparation of this manuscript

REFERENCES

I Atkmson, R L , L K Berke, C R Drake, M L Bibbs, F L Wllhams and D L Kaiser Effects of long-term therapy with naltrexone on body weight m obesity Chn Pharmacol Ther 38, 41%422. 1985 2 Brands, B , J A Thornhdl, M Hlrst and C W Gowdey Suppression of food intake and body weight gain by naloxone in rats LlJe Scl 24: 1773-1778, 1979 3 Davis, W M , T S Mlya and L D Edwards The influence of glucose and msuhn pretreatment upon morphine analgesm in the rat J Am Pharrhacol A~oc 45: 60-62, 1956 4 Hahn, E F and J Fishman Narcotic antagonists Carbon-6 derivatives of N-substituted noroxymorphones as narcotic antagonists J Med Chem 18: 25%262, 1975 5 Levine, A S and J E Morley Pept]derglc control of msuhninduced feeding Pepttdes 2: 261-264, 1981 6 Levine, A S , J E Morley, D M Brown and B S Handwerger Extreme sensmv~ty of diabetic m~ce to naloxonereduced suppression of food intake Phy~iol Behav 28: 987-989, 1982 7 Levine, A S , J E Morley, B A Gosnell, C J Bilhngton and T J Bartness Oplmds and consummatory behavior Brain Re* Bull 14: 663-672, 1985 8 Levme, A S , J E Morley, J Knelp, M Grace and D M Brown Environment modulates naloxone's suppressive effect on feeding in diabetic and non-diabetic rats Physlol Beha~ 34: 391-393, 1985 9 Levme, A S , J E Morley, G Wilcox, D M Brown andB S Handwerger Tail pinch behavior and analgesia In diabetic mice Physlol Behav 28: 3%43, 1982 10 Lowy, M T , R P Maickel and G K W Yim Naloxone reduction of stress-related feeding Life ScI 26:2113-2118, 1980 11 McLaughhn, C L and C A Bade Nalmefene decreases meal size, food and water intake and weight gain m Zucker rats Pharmacol Btochem Behav 19: 235-240, 1983

12 McLaughhn, C L and C A Balle Food intakeandwelghtgam of Zucker rats Increased by autoimmunlzation against fl-endorphin Soc Neurosct Abstr 10: 1015, 1984 13 McLaughhn, C L , C A Bade, R L Gmgerlch and M E Michel Influence of nalmefene on energy balance and glucose regulation in Zucker rats Ph)stol Behav 37: 89%908, 1986 14 Maim, D H , J G Leavell, K Freeman, W C Klnzlerand M A Reagan Continuousmfuslonofnaloxone Effects onbehavlor and oxygen consumption Pharmacol Btochem Behav 22: 791-795. 1985 15 Mandenoff, A , M Apfelbaum, F Fumeron and D L Margules Endogenous opiates and energy balance Scwnce 215" 1536-1538, 1982 16 Marks-Kaufman, R , T BalmaglyaandE Gross Modifications in food retake and energy metabolism m rats as a function of chronic naltrexone Infusions Pharmaco/ Btochem Behav 20: 911-916, 1984 17 Mitchell, J E , J E Morley, A S Levlne, D Hatsukami, M Gannon and D Pfohl High-dose naltrexone therapy and dietary counseling for obesity Biol Psych~ato' 22: 35-42, 1987 18 Morley, J E and A S Levine Cortlcotropm releasing factor, grooming and ingestive behavior Life Scl 31: 145%1464, 1982 19 Morley, J E , A S Levme, B A Gosnelland C J Billington Which opioid receptor mechanism modulates feeding~ Appetite 5: 61-68, 1984 20 Morley, J E , A S Levme, M Grace and J Knelp Aninvestigation of the role of kappa opiate receptor agomsts m the initiation of feeding Life Scl 31: 2617-2626, 1982 21 Morley, J E , A S Levine, G K W Y l m a n d M T Lowy OpIoId modulation of appetite Neuro~cl Btobeha~ Re~ 7: 281305, 1983

500

22 Morley, G K , A D Mooradlan, A S Levme and J E Morley Why is diabetic peripheral neuropathy painful ~ The effect of glucose on pare perception m humans Am J Med 77: 7%82, 1984 23 Recant, L , N R Voyles, M Luclano and C B Pert Naltrexone reduced weight gain, alters "fl-endorphm," and reduces msuhn output from pancreatic islets of genetically obese mlce Pepttdes 1: 30%313. 1980 24 Richter, W O , P Kerscher and P Schwandt /3-hpotropm mcreases ketone body plasma concentration m rabb~ts Neuropepndes 4: 167-173, 1984 25 Rowland, N and T J Bartness Naloxone suppresses msuhnreduced food retake m novel and famdar enwronments, but does not affect hypoglycemia Pharmacol B~ochem Behav 16: 10011003, 1982 26 Shlmomura, Y , J Oku, Z Ghck and G A Bray Opmte receptors, food intake and obesity Phystol Behav 28: 441-443, 1982

LEVINE ET AL

27 Shook, J E and W L Dewey Morphine dependence and diabetes I The development of morphine dependence m streptozotocm-dlabetlc rats and spontaneously dmbettc C57BL/KsJ mice J Pharmacol Exp Ther 237: 841-847, 1986 28 Shook. J E , J F Kachur, D A Brase and W L Dewey Morphine dependence and diabetes II AlteraUons of normorphme potency m the gulnea-p~g ileum and mouse vas deferens and of deal morphine dependence by changes m glucose concentratlon J Pharmacol Erp Ther 237: 848--852, 1986 29 Simon, G S , J Borzelleca and W L Dewey Narcotics and diabetes II Streptozotocm-lnduced diabetes selectively alters the potency of certain narcotic analgesics Mechamsm of diabetes Morphine interaction J Pharmacol Exp Ther 218: 324329, 1981 30 Simon, G S and W L Dewey NarcoUcs anddlabetes I The effects of streptozotocm-lnduced diabetes on antlnoc~cepttve potency of morphine J Pharmacol Exp Ther 218:318-323, 1981 31 Werther, G A and A Hogg Abstract from The Neural and Metabohc Bases oJ Feeding, a symposmm presented by the Umverslty of Cahfornla, Davis, Napa Valley, CA, 1984, p 16