Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.     

Observational analysis of the effects of kappa opioid agonists on open field behaviour in the rat

An observational analysis of the effects of four kappa-opioid agonists on forward locomotion, rearing and grooming displayed by rats in a novel open field was undertaken. The doses of agonists used corresponded to those previously found to produce changes in food consumption. Ethylketocyclazocine (0.1 and 1 mg/kg), bremazocine (0.01 and 0.1 mg/kg) and tifluadom (0.3 and 3 mg/kg) exerted suppressant effects on all the activities monitored. Grooming behaviour appeared to be particularly sensitive to this action, being virtually abolished by the larger doses of these compounds. In contrast, the selective kappa agonist U-50,488H (0.1–3 mg/kg) only attenuated grooming at the two highest doses tested (1 and 3 mg/kg). None of the agonists tested produced stimulation of open field activity during the 1-h study. Reductions in activity occurred at doses previously found to increase and decrease food intake. It was therefore concluded that the hyperphagia induced by kappa agonists was not part of a more general behavioural activation, whilst reductions in food consumption probably result from a non-specific behavioural depression. Offprint requests to: S.J. Cooper     

A2A adenosine receptor agonists reduce both high-palatability and low-palatability food intake in female rats

The present study examined the effect of two A2A adenosine receptor (AR) agonists, CGS 21680 and VT 7, on high-palatability food (HPF) intake in a model of binge eating in sated rats and on low-palatability food (LPF) intake in food-deprived rats. Binge eating was induced in female rats by three 8-day cycles of food restriction/refeeding, followed by acute stress. Two groups of rats were used: NR+NS rats normally fed and not stressed and R+S rats exposed to cycles of food restriction/refeeding and then stressed. R+S rats had higher intake of HPF than the NR+NS controls. The two A2AAR agonists were tested at doses of 0.1 and 0.05 mg/kg intraperitoneally; VT 7 did not modify locomotor activity at either dose, whereas CGS 21680 only slightly reduced it at the higher dose tested. The injection of 0.1 mg/kg of both agonists markedly reduced HPF intake both in R+S and in NR+NS rats. The dose of 0.05 mg/kg was inactive. CGS 21680 and VT 7, 0.1 mg/kg, also reduced the standard LPF intake in 24 h food-deprived rats; however, they did not reduce water intake, indicating that their effect on food intake is selective. The dose of 0.05 mg/kg was inactive. Thus, A2AAR agonists exert a rather general effect on food intake, inhibiting both HPF intake in sated rats and LPF intake in food-deprived rats. They may potentially be useful pharmacological agents to control binge-related eating disorders and to reduce food overconsumption associated with obesity.     

Effect of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidin) cyclohexyl]-benzeneacetamide (U-50,488H), a kappa opioid receptor agonist, on intake of food in food-deprived and non-deprived spontaneously hypertensive and normotensive Wistar-Kyoto rats

The effect of U-50,488H, a selective kappa opioid receptor agonist on the intake of food in food-deprived and non-deprived spontaneously hypertensive and normotensive Wistar-Kyoto rats was determined. In food deprived Wistar-Kyoto rats, intraperitoneal administration of U-50,488H, produced a bell-shaped curve on the intake of food, consistent with earlier reports in the literature. Thus, at a dose of 0.1 mg/kg there was a significant increase in the intake of food and at 10 mg/kg it caused a decrease in the intake of food, at 2, 4 and 6 hr after the treatment with drug. The amount of food consumed at each dose and the time interval was greater in hypertensive rats than in Wistar-Kyoto rats. Similar effects were produced when the animals were not deprived of food. The basal intake of food in the two strains of rats did not differ. The results indicate a greater sensitivity of spontaneously hypertensive rats to kappa opioid receptor agonists and further the previous observations that compared to Wistar-Kyoto rats, the hypertensive rats have a greater density of central kappa opioid receptors.     

Parametric studies of selective D1 or D2 antagonists: effects on appetitive and feeding behaviour

Dopamine receptor antagonists have long been known to suppress food intake. The main purpose of the present series of experiments was to investigate feeding in rats across several paradigms evaluating the effects of selective dopamine D1 and D2 antagonists. The selective D1 antagonist, SCH 23390, reduced FR8 operant responding for food (0.03mg/kg, s.c.) at a dose lower than that required to reduce food intake in two free-feeding situations (0.1mg/kg, s.c.). The selective D2 antagonist, YM 09151-2, had a biphasic effect on food intake in food-deprived rats, increasing food intake at a low dose (0.01mg/kg, i.p.), but decreasing intake at higher doses in deprived rats (0.1mg/kg, i.p.). A combination of subthreshold doses of SCH 23390 and YM 09151-2 resulted in a significant reduction in food intake. In nondeprived rats eating palatable food and in animals trained on an FR8 schedule of reinforcement, YM09151-2 exerted significant suppressant effects. The results suggest that the operant response is more sensitive to the effects of selective D1 and D2 antagonism than is the consummatory response. The findings also suggest a specific inhibitory role for dopamine D2 (and not D1) receptors on food intake, since selective D1 antagonism did not produce increases in food intake at any of the doses tested. This provides evidence that under some circumstances the effects of D1 and D2 receptor blockade are dissociable.     

Novel benzodiazepine receptor ligands: palatable food intake following zolpidem, CGS 17867A, or Ro23-0364, in the rat

The potent imidazopyridine hypnotic, zolpidem, binds to central benzodiazepine receptors and has predominantly sedative properties, as determine in animal models. In tests of palatable food consumption in nondeprived male rats, the present results indicate that zolpidem (0.3-3.0 mg/kg) had no effect on food intake. Its lack of effect contrasts sharply with other benzodiazepine agonists which strongly stimulate palatable food intake. Two other novel compounds, both of which bind to benzodiazepine receptors, and which have reduced propensity to induce sedative effects, increased palatable food consumption, although in differing ways. The imidazobenzodiazepine Ro23-0364 (0.3-10.0 mg/kg) dose-dependently increased feeding in the standard procedure, but failed to stimulate food intake in presatiated animals. The pyrazoloquinoline CGS 17867A (1.0-30.0 mg/kg) increased food intake in both test procedures, although the dose-effect relationship was nonmonotonic. Taken together, the data indicate a probable separation between hyperphagic and sedating effects of benzodiazepine receptor agonists. If zolpidem's sedative effect is linked to an action at a receptor subtype (benzodiazepine Type 1 or omega 1), then the hyperphagic effect of benzodiazepines may depend more on the alternative subtype.     

Differential antagonism of the rate-decreasing effects of kappa-opioid receptor agonists by naltrexone and norbinaltorphimine.

Eight kappa-opioid receptor agonists were examined for their effects in squirrel monkeys responding under a fixed interval 3-min schedule of stimulus termination. Six of these kappa-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with kappa-opioid receptor interaction. Three of these kappa-opioid receptor agonists, bremazocine, U69,593 [[(5a,7a,8b)-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)] benzeneacetamide] and enadoline, were evaluated following pretreatment with 1.0 mg/kg of naltrexone or 3.0 mg/kg of norbinaltorphimine. The effects of the three agonists were antagonized significantly by naltrexone, but only those of bremazocine and U69,593 were antagonized significantly by norbinaltorphimine. Statistical analysis of the data averaged over six monkeys revealed that naltrexone was significantly more potent than norbinaltorphimine at antagonizing enadoline and U69,593, but naltrexone and norbinaltorphimine were equipotent at antagonizing bremazocine. Moreover, naltrexone was 8-fold more potent at antagonizing U69,593 and enadoline than at antagonizing bremazocine. These results suggest that under these conditions the effects of U69,593 and enadoline may be mediated, in part, by a different receptor population, perhaps a subtype of kappa-opioid receptors, from the one that mediates the effects of bremazocine.     

Hyperphagic and anorectic effects of ß-carbolines in a palatable food consumption test: Comparisons with triazolam and quazepam

The triazolobenzodiazepine triazolam (0.1–1.0 mg/kg i.p.) and quazepam (0.3–30.0 mg/kg i.p.) were administered to non-food-deprived rats which had been partially-satiated on a palatable diet. In a subsequent 30 min feeding test, both compounds produced a significant increase in the level of food consumption. While triazolam had a dose-related effect and produced a 151.5% increase in the level of food intake, quazepam exerted only a partial effect, achieving a 73.9% increase in food intake at 3.0 mg/kg but no additional increase in food intake at higher doses. The two β-carbolines, ZK 93423 (0.1–3.0 mg/kg i.p.) and ZK 91296 (1.0–30.0 mg/kg i.p.), a full agonist and a partial agonist at benzodiazepine receptors respectively, also produced significant increases in food consumption under the same experimental conditions. ZK 93423 had effects which were similar to those of triazolam, ZK 91296 had effects similar to quazepam. The β-carboline benzodiazepine inverse agonist FG 7142 (10.0 mg/kg i.p.) had an anorectic effect in non-food-deprived rats given 30 min access to the highly palatable diet. This effect was reversed by the β-carboline benzodiazepine receptor antagonist ZK 93426 in a dose-dependent manner. These results emphasize that within the series of β-carboline ligands for benzodiazepine receptors, their characterization in terms of agonists, antagonists and inverse agonists has validity with respect to the behavioural response of palatable food consumption in non-food-deprived rats.     

Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity

To better understand the influence of kappa-opioid agonists on the effects of cocaine, rats were treated with daily injections of the selective kappa-opioid agonist U-69593 or bremazocine. In combination with 10 mg/kg cocaine, both compounds, at a dose of 0.32 mg/kg, greatly diminished locomotor activity, and these effects were maintained over a period of 5 days. In addition, the response to a challenge injection of 10 mg/kg cocaine several days after the end of kappa-Opioid agonist treatment with or without cocaine was markedly reduced. When naltrexone was given in combination with U-69593, it blocked the reduction in cocaine-induced locomotor activity after U-69593 treatment alone. However, a single injection of either kappa-opioid agonist alone had no effect on cocaine-induced locomotion several days later (i.e. no long-term effects), suggesting that multiple injections of the kappa-opioid agonist are needed to reduce the locomotor activating effects of cocaine other than acutely. In addition, treatment with the kappa-opioid agonist U-69593 (0.32 mg/kg) over a 5-day period decreased dopamine transporter densities in the caudate putamen, and this was also blocked by co-administration of naltrexone.     

The selective dopamine D1 receptor agonist SK&F 38393: its effects on palatability- and deprivation-induced feeding, and operant responding for food

A series of experiments investigated the involvement of the dopamine D1 receptor subtype in relation to feeding responses. The selective D1 agonists, SK&F 38393 (1.0-20 mg/kg) and SK&F 75760 (5 mg/kg), significantly reduced palatable food consumption in nondeprived rats. The anorectic effect of SK&F 38393 (10 mg/kg) was additive with that of the selective D2 receptor agonist, N-0437 (0.3 mg/kg). In nondeprived mice, SK&F 38393 had a stereoselective effect to reduce palatable food intake. At a peripherally-selective dose (3.0 mg/kg), the peripheral dopamine D1 receptor agonist, fenoldopam, had no effect on food intake. At 10 mg/kg, however, it exhibited anorectic properties, although this may have been due to some penetration of the blood-brain barrier. In rats adapted to a food-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) produced significant dose-dependent reductions in consumption of powdered chow and in lever-pressing for food pellets on a FR8 schedule of reinforcement. In rats adapted to a water-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) was substantially less effective in reducing water intake. The results are discussed in terms of a possible selective effect of D1 agonist activity on feeding behaviour.     

Effects of tifluadom on food consumption compared with chlordiazepoxide and kappa agonists in the rat

Tifluadom (0.625-10.0 mg kg-1) was administered to non-deprived male rats which had been accustomed to eating a highly palatable diet in a 30 min test period. This compound, an opioid benzodiazepine, produced a significant increase in consumption of food when administered by the subcutaneous route, but not after intraperitoneal injection. Both chlordiazepoxide (1.25-20.0 mg kg-1) and the selective kappa opiate receptor agonist U-50,488 (0.3125-2.5 mg kg-1) also produced significant hyperphagic effects in the same feeding situation. In contrast, the two kappa opiate receptor agonists, ethylketocyclazocine (0.1-3.0 mg kg-1) and bremazocine (0.078-1.25 mg kg-1) brought about a dose-related suppression of food intake. Hence, the effects of kappa opiate receptor agonists in the feeding situation described here were not uniform. Furthermore, tifluadom could be likened either to a benzodiazepine or to a selective kappa receptor agonist. The hyperphagia induced by tifluadom was antagonized by naloxone, suggesting that the effect was mediated by an action at opiate receptors. It was not antagonized however by Ro15-1788 (10.0 and 20.0 mg kg-1), a selective benzodiazepine receptor antagonist, ruling out possible mediation by benzodiazepine receptors. The benzodiazepine receptor antagonist, CGS 8216, exhibited intrinsic activity when administered alone, and significantly reduced food consumption in tifluadom-treated and control animals.     

Antidiuretic effect of bremazocine and U-50,488 in rats after alpha 2-adrenoceptor blockade.

The role of alpha 2-adrenoceptors and kappa-opioid receptors in urination was studied in rats. In water-loaded rats (40 mL kg-1 p.o.) the kappa-opioid agonist bremazocine (0.05 0.2 mg kg-1 i.p.) induced a dose-related diuretic response in the second hour after administration, but had no effect in the first hour. When rats were pretreated with the alpha 2-adrenoceptor antagonist idazoxan (1 mg kg-1 s.c.), bremazocine induced a dose-related antidiuretic response in the first hour; thereafter the rats showed an increase of urination similar to that with bremazocine alone. The antidiuretic effect of bremazocine was dependent on the dose of idazoxan with maximal response after 1-3 mg kg-1. Similar results were obtained with bremazocine in the presence of yohimbine (1 mg kg-1 s.c.). The antidiuretic profile of bremazocine after idazoxan was shared by U-50,488 (2.5-10 mg kg-1 i.p.), although this compound alone at the high dose reduces urine output in the first hour. The antidiuresis induced by bremazocine in the presence of idazoxan in water-loaded rats was completely antagonized by 10 but not 2 mg kg-1 i.p. of the opioid antagonist naloxone. Thus, kappa-opioid agonists, in addition to their diuretic effect, also produce an antidiuretic response which may be mediated by alpha 2-adrenoceptors.     

Kappa-opiates and urination: pharmacological evidence for an endogenous role of the kappa-opiate receptor in fluid and electrolyte balance

In prehydrated rats, the administration of kappa-opiate agonists such as bremazocine, ethylketocyclazocine or compound Upjohn-50,488 produced a dose-dependent increase in urine output and decreased the concentration of Na+ and K+ in the urine as compared to that of saline-treated rats. The diuretic effect of bremazocine lasted at least 3 h. The increase in urine output was independent of the hydration state of the rat since in non water-loaded animals, bremazocine produced proportionally as much diuresis and a decrease in the output of urine electrolytes of about the same magnitude as that observed in the prehydrated animals treated with the opioid. In contrast to the diuretic action of kappa-opiate agonists, the administration of antagonists with high affinity for the kappa-opiate receptor (Win 44,441 or Mr 2266) decreased dose dependently the output of urine and reduced very significantly the total output of Na+ and K+. Whereas 2 mg/kg naloxone did not block the bremazocine-induced urinary effects, 1 mg/kg Win 44,441 or Mr 2266 antagonized competitively the renal activity of bremazocine. The results are interpreted to suggest that the kappa-opiate receptor may be involved in the regulation of fluid and electrolyte balance.     

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a twochoice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC aue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct muopioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1–1.0 mg/kg naloxone, whereas doses of naloxone 3–10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opiod and kappa-opioid components that can be separated using antagonists such as naloxone.     

Differential effects of two cannabinoid receptor agonists on progressive ratio responding for food and free-feeding in rats

The cannabinoid receptor agonists delta9-tetrahydrocannabinol (delta9-THC) and HU-210 were compared in terms of their effects on: (1) progressive ratio (PR) responding for food, and (2) free food intake. In the first experiment, food-deprived Wistar rats were trained on a time-constrained (60 min) PR-5 schedule for food reinforcement, in which the response requirement incremented by five lever presses for each successive reinforcer. One group of rats received vehicle, 0.5, 1 or 3 mg/kg delta9-THC (i.p.), and three other groups received HU-210 (i.p.) at three different dose ranges, spanning 0.001-0.1 mg/kg. In the second experiment, the effects of the two drugs on free food intake were tested in a separate group of non-deprived rats. For PR responding, delta9-THC significantly increased the break point (final ratio completed) and the total number of lever presses emitted. The same drug also significantly increased free food intake. However, the effects of HU-210 were quite different: it did not alter PR responding at any dose; instead, its only significant effect was to reduce free food intake at 0.06 mg/kg. These data suggest that increased motivation to obtain food might underlie the hyperphagic effects of delta9-THC. However, the synthetic agonist HU-210 has different effects: it only acts to reduce feeding behaviour, an outcome that probably reflects non-specific behavioural disruption. These findings suggest important differences between the two CB1 receptor agonists in terms of their pharmacological effects.     

Nor-binaltorphimine: an ultra-long acting kappa-opioid antagonist in pigeons

This study assessed the ability of naltrexone and nor-binaltorphimine (NBNI) to antagonize the rate-decreasing effects of opioid agonists. Food-restricted pigeons were trained to peck a lit key under a fixed-ratio (FR) 20 schedule of food reinforcement. Bremazocine, a kappa-opioid agonist, decreased food-reinforced responding (ED(50) = 0.02mg/kg), and naltrexone (5.6mg/kg) reduced the potency of bremazocine six-fold. The effect of naltrexone lasted less than 24h. A single injection of NBNI (1mg/kg) was given to four pigeons, and the time course of antagonism of the rate-decreasing effects of bremazocine was measured. One hour after NBNI was given, it was ineffective. Eight days later, NBNI produced a five-fold reduction in the potency of bremazocine. Between 12 and 20 days after NBNI, it reduced the potency of bremazocine 14-fold. NBNI continued to antagonize bremazocine for 11 weeks. Smaller doses of NBNI (0.001-0.1mg/kg) were ineffective. The effect of NBNI was not due to tolerance to bremazocine, since tolerance failed to develop to bremazocine administered repeatedly. NBNI (1mg/kg) did not antagonize the response rate-decreasing effects of morphine, a mu-opioid agonist, or BW373U86, a delta-opioid agonist. NBNI was an effective and extremely long-lasting kappa-opioid antagonist in the pigeon. The duration of action of NBNI is among the longest yet described in any species.     

Effects of intraperitoneal administration of the GABA B receptor agonist baclofen on food intake in rats measured under different feeding conditions

The effects of intraperitoneal (i.p.) administration of the GABA(B) receptor agonist baclofen were assessed in rats under different feeding conditions. In Experiment 1, it was observed that baclofen (1-4 mg/kg) significantly (at least, P<0.05) increased cumulative food intake in non-deprived rats during the 120 min measurement period during the early light phase of the light-dark cycle. By contrast, during the early dark phase of the light-dark cycle in non-deprived rats, the 1mg/kg doses of baclofen significantly increased cumulative feeding at 30, 60 and 120 min (at least P<0.05), the 2mg/kg dose significantly increased feeding at 30 and 60 min (at least P<0.05) and the 4 mg/kg dose had no effects on feeding. In Experiment 2, baclofen (1-4 mg/kg) was found to produce no significant effects on food intake in rats that were food-deprived for 22 h. In Experiment 3, the effects of baclofen were investigated on food intake in 16 h food-deprived rats that had received an oral preload for 2h prior to drug administration. Baclofen (1-4 mg/kg) significantly increased cumulative food consumption (at least, P<0.05) only during the first 30 min after administration in these animals. The results of this study indicate that the effects of baclofen on food intake may be related to the state of hunger or satiety of the animals and the time during the light-dark cycle when the drug is administered.     

Effects of mu- and kappa-opioid receptor agonists on urinary output in mice

The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3--10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.     

Feeding responses to mu-, delta- and kappa-opioid receptor agonists in the meat-type chick

The present study was designed to examine the effect of specific opioid agonists on feeding behavior in neonatal chicks. The food intake of broiler chicks was significantly decreased by intracerebroventricular injection of DAMGO and beta-casomorphin, micro-opioid receptor agonists, at 30-min postinjection. In contrast, both delta-opioid receptor agonists (DADLE and DPDPE) stimulated the food intake of the chick. Similar to the delta-opioid receptor agonists, food intake was elevated by the kappa-opioid receptor agonist (U-50488H and U-62066) in a dose-dependent manner. These results suggest that the endogenous opioid peptides have an important role for feeding behavior in the central nervous system of chicks.     

Opioids and rate of positively reinforced behavior: differential antagonism by naltrexone

Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food presentation. The response rate-decreasing effects of several opioid compounds that vary in selectivity for, and activity at, μ, kappa, and non-opioid receptors, were examined alone and in combination with the opioid antagonist naltrexone. Naltrexone (0.01-1.0mg/kg) produced dose-dependent and generally parallel rightward shifts in the dose-effect curves for morphine, fentanyl, butorphanol and nalbuphine. Apparent pA(2) values for naltrexone against these agonists ranged from 7.05 to 7.29, and the slopes of the regression lines fitted to the Schild plots approximated theoretical unity (-1.0), suggesting a competitive interaction at μ-opioid receptors. In contrast, although at least one dose of naltrexone (0.01-10.0mg/kg) antagonized the response rate-decreasing effects of bremazocine, U50,488, (-)-pentazocine and nalorphine, suggesting some opioid activity, these effects differed from those of the μ agonists in that: (a) they were less sensitive to naltrexone antagonism; (b) maximal rightward shifts were smaller; (c) antagonism patterns were not directly related to naltrexone dose and, in some cases, were influenced by the response rate-decreasing effects of the larger naltrexone doses; and (d) there were considerable between-subjects differences in sensitivity to naltrexone antagonism. Naltrexone (0.1-10.0mg/kg) did not antagonize the effects of the non-opioid control compound pentobarbital. The present results suggest that patterns of naltrexone antagonism can provide a basis for making inferences about receptor activity related to the effects of some opioids on rate of schedule-controlled behavior. With some opioids, however, such inferences are limited by the direct response rate-decreasing effects of naltrexone itself and by differences in patterns of antagonism across subjects.