Evaluation of the <Emphasis Type="Italic">mu</Emphasis> and <Emphasis Type="Italic">kappa</Emphasis> opioid actions of butorphanol in humans through differential naltrexone blockade

Rationale Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans. Objectives The aim of this study was to determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu vs kappa receptors. Materials and methods Ten healthy adult inpatient volunteers (eight men, two women), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10, or 30 mg, p.o.) was administered 1 h before butorphanol (0, 6, or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, and subject- and observer-rated) measures was collected before and for 4 h after drug administration. Results Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., “liking,” “good drug effects”) and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanol-induced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of subjective responses. Conclusion These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu vs kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.     

Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys

As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((+/-)-1-[2,3- (Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments.     

Butorphanol agonist effects and acute physical dependence in opioid abusers: comparison with morphine

This study compared the direct effects and acute physical dependence of butorphanol and morphine, opioids with differing actions at mu versus kappa receptors. Six non-dependent heroin-using volunteers were exposed to six conditions in a within-subject, Latin square design using double-blind procedures. In each session, agonist effects of single i.m. injections of butorphanol (3 and 6 mg/70 kg), morphine (15 and 30 mg/70 kg), lorazepam (4 mg/70 kg) or saline were evaluated. Butorphanol and morphine produced effects of comparable magnitude on miosis and reports of 'any drug effect'. Volunteers reported dysphoria, confusion and sedation after butorphanol, subjective effects that overlapped with those of lorazepam, whereas morphine produced euphoria and stimulation. Acute physical dependence (i.e. precipitated withdrawal responses to naloxone 10 mg/70 kg i.m. administered 6 h after each treatment) significantly increased after 30 mg/70 kg morphine but not after butorphanol treatments. These differences in naloxone sensitivity are likely due to differences in opioid receptor (mu versus kappa) activity, affinity and efficacy of these compounds. Pharmacological ramifications of these results are discussed.     

Modulation of the discriminative stimulus effects of d-amphetamine by mu and kappa opioids in squirrel monkeys

It has been reported that the discriminative stimulus effects of cocaine in squirrel monkeys can be potentiated by mu opioid agonists and attenuated by kappa opioid agonists. The purpose of this study was to extend these observations by examining the effects of mu and kappa opioids agonists on the discriminative stimulus effects of d-amphetamine (AMPH). Five squirrel monkeys were trained to discriminate 0.3 mg/kg of AMPH (i.m.) from saline using a stimulus termination/avoidance task. AMPH and cocaine substituted dose dependently for the AMPH training stimulus in all five monkeys. The AMPH training dose was completely antagonized by 0.1 mg/kg of the D1 dopamine antagonist SCH 39166. When administered alone, the kappa agonist U69,593 substituted partially or completely for AMPH in four of five monkeys, the kappa agonist enadoline substituted completely for AMPH in two of five monkeys, and morphine substituted completely for AMPH in one monkey. In all five monkeys, pretreatment with some doses of U69,593 or enadoline attenuated the discriminative stimulus effects of AMPH; however, some doses of U69,593 and enadoline also potentiated the effects of AMPH in at least two monkeys. Morphine pretreatment potentiated the discriminative stimulus effects of AMPH in three monkeys and either attenuated or did not alter these effects in two monkeys. Morphine pretreatment did not significantly alter the discriminative stimulus effects of cocaine except in one monkey. These data indicate large individual differences in the abilities of mu and kappa opioid agonists to alter the discriminative stimulus effects of AMPH.     

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.     

Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers

Buprenorphine is a mu opioid partial agonist currently used as an analgesic, and being developed for the treatment of opioid dependence. The purpose of this study was to determine the abuse liability of parenteral buprenorphine in volunteers maintained on daily sublingual (SL) buprenorphine (8 mg). In a residential laboratory, eight volunteers underwent pharmacologic challenges two times per week. Medication challenges were 16 h after the daily dose of buprenorphine, and consisted of double-blind IM injections of buprenorphine (4, 8, 16 mg), the prototypic mu opioid agonist hydromorphone (9 and 18 mg), or saline. Assessments consisted of physiologic monitoring, subjects’ self-reports, and a trained observer’s ratings of drug effects, and were collected for 0.5 h before and 2.0 h following injection. Supplemental doses of IM buprenorphine produced opioid agonist-like effects, indicating some abuse potential of parenteral buprenorphine in buprenorphine-maintained patients. There was incomplete cross-tolerance to the effects of hydromorphone, suggesting that higher maintenance doses of buprenorphine may be needed to maximize clinical efficacy. However, there was a lack of graded dose-effects for hydromorphone, suggesting that buprenorphine’s combination of partial agonist effects and high affinity for opioid receptors may limit the magnitude of effects of supplemental full agonists. Finally, participants tolerated cumulative doses of maintenance buprenorphine plus challenge buprenorphine without adverse effects, suggesting higher doses of buprenorphine can be safely administered to opioid dependent patients. Received: 22 February 1996/Final version: 23 August 1996     

Butorphanol's efficacy at mu and kappa opioid receptors: inferences based on the schedule-controlled behavior of nontolerant and morphine-tolerant rats and on the responding of rats under a drug discrimination procedure

The purpose of the present investigation was to characterize the mu agonist and kappa antagonist effects of the mixed opioid agonist/antagonist butorphanol. To this end, the effects of butorphanol were examined: 1) alone and in combination with the kappa agonist bremazocine in nontolerant and morphine-tolerant rats responding under a fixed-ratio 30 (FR30) schedule of food presentation, and 2) in rats trained to discriminate 10 mg/kg morphine from saline. Prior to the induction of morphine tolerance, morphine, bremazocine and butorphanol produced dose-dependent decreases in rate of responding under the FR30. In these nontolerant rats, butorphanol failed to antagonize bremazocine's rate-decreasing effects. During the chronic morphine regimen, the dose-effect curve for morphine was shifted to the right of its prechronic position by approximately 0.9 log units, whereas the bremazocine curve was not altered substantially. The butorphanol dose-effect curve, in contrast, was shifted to the right and flattened such that doses which eliminated responding in nontolerant rats, as well as doses approximately 1.0 log unit higher, had no effect on responding. In these morphine-tolerant rats, butorphanol produced a dose-dependent antagonism of bremazocine's rate-decreasing effects. In rats trained to discriminate morphine from saline, butorphanol substituted completely for the morphine stimulus. Unlike morphine, which produced its stimulus effects only at doses that decreased rate of responding, butorphanol substituted for the morphine stimulus at doses that had little or no effect on rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Discrimination of butorphanol and nalbuphine in opioid-dependent humans.

The purpose of the study was to evaluate the agonist and antagonist stimulus properties of the mixed opioid agonist antagonists butorphanol and nalbuphine in opioid-dependent subjects. Opioid-dependent volunteers (methadone 30 mg/day, PO) were trained in a three-choice drug discrimination procedure to discriminate between the effects of saline (2 ml), hydromorphone (10 mg/70 kg) and naloxone (0.15 mg/70 kg) administered IM. Subjects earned monetary reinforcement for correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were also collected. Hydromorphone and naloxone increased drug-appropriate responses and other characteristic subjective effects measures. Butorphanol and nalbuphine produced increases in naloxone-appropriate discrimination responding and in those subjective effect measures increased by naloxone. Butorphanol produced greater than 80% naloxone-appropriate responding at 1.05 mg/70 kg; nalbuphine produced 100% naloxone-appropriate responding at 2.1 mg/70 kg. Neither butorphanol nor nalbuphine showed opioid agonist-like effects in these subjects maintained at moderate levels of physical dependence. In opioid-dependent subjects, the stimulus effects of butorphanol and nalbuphine are antagonist-like.     

Participation Of Central and Peripheral κ1 and κ2 Opioid Receptors In Arrhythmogenesis

1. The kappa 1 and kappa 2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (-)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The kappa 1 opioid receptor agonists U-50488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the kappa 2 opioid receptor agonist (-)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the kappa opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the kappa opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the kappa 1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system.     

Effects of gonadal steroid hormone treatments on opioid antinociception in ovariectomized rhesus monkeys

RATIONALE: Gonadal steroid hormones altered opioid antinociception under some conditions in rodents, and we reported previously that chronic estradiol enhanced kappa but not mu opioid antinociception in ovariectomized rhesus monkeys. Sex differences have also been observed in the antinociceptive effects of opioid agonists. These findings suggest that gonadal hormones may modulate opioid antinociception. OBJECTIVES: To extend our previous studies of estradiol by examining the effects of progesterone alone, estradiol in combination with progesterone, and testosterone alone on opioid antinociception in ovariectomized rhesus monkeys. METHODS: Opioid effects were studied during chronic treatment with vehicle (sesame oil) or with progesterone alone (P; 0.32 mg/kg per day), a combination of progesterone+estradiol (P+E; 0.32 mg/kg per day P + 0.002 mg/kg per day E), or testosterone alone (T; 0.32 mg/kg per day). Opioid antinociception in a warm-water tail-withdrawal procedure was examined with the selective kappa opioid agonist U50,488, the selective mu agonist morphine, and the two mixed-action opioids butorphanol and nalbuphine. RESULTS: The steroid treatment regimens produced physiological levels of progesterone and estradiol similar to peak levels observed during the luteal phase of the menstrual cycle and physiological levels of testosterone similar to those observed in intact males. Treatment with P, P+E, or T did not alter baseline thermal nociception. P+E significantly increased the potency of U50,488 at 50 degrees C but not at 54 degrees C. Gonadal hormone treatments had little or no effect on antinociception produced by morphine, butorphanol, or nalbuphine at either temperature. CONCLUSIONS: These findings further suggest that chronic treatment with physiological levels of gonadal hormones may modulate the antinociceptive effects of U50,488 in ovariectomized rhesus monkeys.     

Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys.

kappa-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed kappa/mu receptor activity is unclear. The effects of three mixed kappa/mu agonists (MCL-101, (-)cyclorphan, and Mr2034) and one kappa-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all kappa agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (-)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration dose-effect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (-)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed kappa/mu agonists produced fewer side effects (some salivation) than the kappa-selective agonist (sedation, salivation, emesis). However, none of these kappa agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, kappa and mixed kappa/mu-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed kappa/mu agonists appear to offer some advantages over selective kappa agonists as potential treatments for cocaine abuse.     

Effects of buprenorphine/naloxone in opioid-dependent humans

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).     

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine,l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine,l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists. In addition, the lack of cross-tolerance between morphine and the kappa agonists examined demonstrate that this behavioral preparation is a useful tool for differentiating the effects of compounds acting at different opioid receptor types.     

Buprenorphine alone and in combination with naloxone in non-dependent humans

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonistantagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.     

The mu opioid agonist DAMGO alters the intravenous self-administration of cocaine in rats: mechanisms in the ventral tegmental area

 Microinfusions of the opioid subtype-selective agonist DAMGO and antagonist CTOP into the ventral tegmental area (VTA) were used to examine the role of mu opioid receptors in this area of the mesolimbic dopamine system in regulating cocaine reinforcement. Long-Evans rats were trained to self-administer cocaine intravenously and prepared with intracranial cannulae directed to the VTA. At doses of cocaine on the descending limb of the cocaine dose-response curve, the mu-selective agonist DAMGO produced a dose-related decrease in cocaine self-administration when delivered by microinfusion into the VTA. At a dose of cocaine on the ascending limb of the self-administration dose-response curve, DAMGO microinfusions produced an increase in responding for the drug. The mu-selective antagonist CTOP produced small effects on cocaine self-administration. A kappa-selective agonist and antagonist (U50,488 and norbinaltorphimine, respectively) produced either no effects or small effects that did not show consistent trends with dose. These experiments suggest that the mu agonist DAMGO is able to shift the dose-response curve for cocaine self-administration to the left. This effect appears to be specific for mu as compared to kappa agonists. These data are consistent with the known differential distribution of opioid receptor subtypes within the VTA, and with the effects of opioid compounds in the VTA on dopamine release in the mesolimbic synaptic field. The data show that a mu opioid mechanism in the somatodendritic region can alter reinforcement processes for cocaine, which acts predominantly at the terminal field of dopamine cells. Received: 8 May 1998 / Final version: 13 August 1998     

Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human

Background:

Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.

Methods:

Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.

Results:

In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4–10mg).

Conclusions:

We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.     

Three-choice discrimination in pigeons is based on relative efficacy differences among opioids

RATIONALE: Drug discrimination assays can provide important information on receptor selectivity and relative efficacy to guide the classification and characterization of opioid agonists. OBJECTIVES: A three-choice discrimination was established among high efficacy opioid agonist morphine, low efficacy opioid agonist nalbuphine, and saline to examine the conditions under which differences in relative efficacy might serve as a basis for stimulus control. METHODS: Seven White Carneau pigeons were trained to discriminate among 5.6 mg/kg nalbuphine, 3.2 mg/kg morphine, and saline under fixed ratio 30 (FR30) schedules of food reinforcement. Substitution and antagonism experiments were then conducted with mu, kappa, and delta opioids and naltrexone, respectively and the percent responding appropriate to the training stimuli was determined. RESULTS: Low, intermediate, and high doses of morphine produced > or = 80% saline-, > or = 60% nalbuphine-, and > or = 96% morphine-appropriate responding, respectively. Low and high doses of nalbuphine produced > or = 80% saline- and nalbuphine-appropriate responding, respectively. In substitution tests, low doses of fentanyl and etorphine produced partial nalbuphine-appropriate responding (20-60%) and high doses produced > or = 60-80% morphine-appropriate responding. Intermediate doses of buprenorphine and dezocine produced > or = 60-80% nalbuphine-appropriate responding and high doses produced > or = 80% morphine-appropriate responding. The lower efficacy agonists butorphanol, nalorphine, and levallorphan produced > or = 40-80% nalbuphine-appropriate responding. The kappa agonists spiradoline and U50,488 produced approximately > or = 50% nalbuphine-appropriate responding whereas d-amphetamine, saline, and delta agonists BW373U86 and SNC 80 produced > or = 80% saline-appropriate responding. Naltrexone produced > or = 80% saline-appropriate responding and reversed the stimulus effects of morphine and nalbuphine. CONCLUSIONS: The discrimination between morphine and nalbuphine in pigeons is predominantly based on the relative efficacy differences between morphine, a higher-efficacy mu agonist and nalbuphine, a lower-efficacy mu agonist.     

Tolerance and cross-tolerance to the rate-suppressing effects of opioids in butorphanol-treated rats: influence of maintenance dose and relative efficacy at the mu receptor

 The purpose of the present investigation was to examine the development of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of butorphanol, an opioid with low relative efficacy at the mu receptor. The mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufentanil, and the kappa opioid U50,488 dose-dependently suppressed responding under all conditions examined. In rats administered the low maintenance dose of butorphanol, tolerance developed to the effects of butorphanol, buprenorphine and morphine, but not to fentanyl and sufentanil. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degree to which tolerance developed was greater for butorphanol and buprenorphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats administered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when tested at both 23 and 47 h following the previous maintenance dose of butorphanol, suggesting that these changes were not due to any acute pharmacological interactions between butorphanol and the test compound (i.e., antagonism). Tolerance was also conferred to the kappa opioid U50,488 in both groups of rats, and in rats administered the high maintenance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence developed in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-suppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependence was apparent in rats administered the low maintenance dose of butorphanol. These data suggest that during chronic treatment with butorphanol, (1) greater degrees of tolerance are conferred to drugs possessing low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opioid dependence. Received: 25 November 1997 / Final version: 21 February 1998     

The kappa opioid receptor and food intake

Many studies have suggested a role of opioid receptors in the modulation of food intake. Several distinct classes of opioid receptors have been postulated. In an attempt to establish which opioid receptor(s) modulate feeding we studied the effect of the kappa agonist, bremazocine, on feeding and compared its effects to the preferential mu agonist, morphine, and the mixed kappa-sigma agonist, butorphanol and the kappa agonist, ethylketocyclazocine. Bremazocine increased feeding to the same extent as morphine and was less potent than the mixed agonist/antagonists. The bremazocine effect demonstrated a bell-shaped dose response curve. Daily administration of bremazocine or morphine enhances the effect on increasing food intake. However, this effect of daily injections on enhancing food intake is not present when animals receiving morphine are crossed over to bremazocine and vice versa. The bremazocine effect is enhanced by diprenorphine and not inhibited by naloxone. Low doses of the dopamine antagonist, haloperidol, enhance the bremazocine effect and higher doses inhibit it. Finally, using another kappa agonist, tifluadom, we showed that the effect on food intake is stereospecific. Our studies provided further evidence for a role for the kappa opioid receptor in feeding. However, they also suggest that more than one subpopulation of opioid receptors is involved in feeding modulation.     

Butorphanol and nalbuphine in opioid-dependent humans under a naloxone discrimination procedure.

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e., Drug A) and placebo (i.e., Drug B) under an instructed novel-response drug-discrimination procedure in which subjects identify the drug condition as "A," "B," or "N" (neither A nor B--'novel'). Once the discrimination was acquired, doses of naloxone (000.15 mg/70 kg, i.m.) and the mixed-action opioid agonist/antagonists butorphanol (0-1.5 mg/70 kg, i.m.) and nalbuphine (0-3.0 mg/70 kg, i.m.) were tested. Naloxone produced dose-related increases in naloxone-appropriate responding with little or no 'novel'-appropriate responding. Butorphanol produced a dose-related increase in naloxone- and 'novel'-appropriate responding, occasioning approximately 70% and 29%, respectively, at the highest dose tested. Nalbuphine produced 40-65% naloxone-appropriate responding at all doses tested and 33% 'novel'-appropriate responding at the highest doses. Self-reported effects produced by each agent differed only slightly. These results suggest that mixed-action opioid agonist/antagonists may be distinguished from the opioid antagonist naloxone based on their discriminative-stimulus effects under a novel-response naloxone discrimination procedure.