buprenorphine and clocinnamox

The slow association and incomplete dissociation of buprenorphine from opioid receptors observed in vitro have been suggested to reduce the accessibility of opioid receptors in vivo. If so, it might be expected that buprenorphine continues to occupy opioid receptors long after the antinociceptive activity has dissipated. To examine this hypothesis, buprenorphine (46.4 microg/kg i.v.) was administered to rats 1, 2, 4 or 8 h before isolation of their forebrain membranes and the maximal binding capacity (Bmax) for [3H]-[D-Ala2, N-methyl-Phe4-Gly5-ol]-enkephalin ([3H]DAMGO) was determined to measure the number of mu-opioid receptor binding sites remaining. Extent and duration of the reduction of Bmax by buprenorphine (ED50 11.2 microg/kg 1 h post-application) correlated with the antinociceptive activity in the rat tail flick (ED50 16.4 microg/kg i.v. 1 h post-application). At 8 h after administration there was still residual antinociception but no further attenuation of Bmax was detectable. Thus receptor occupancy by buprenorphine does not cause impairment of mu-opioid receptor accessibility beyond the duration of its antinociceptive activity. Therefore, no impairment of antinociception in the case of an opioid switch is to be expected.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Buprenorphine; Cinnamates; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Kinetics; Models, Animal; Morphine; Morphine Derivatives; Narcotic Antagonists; Pain; Pain Measurement; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Electrophysiological studies have demonstrated a physiological interaction between 5-HT2A and mu-opioid receptors in the medial prefrontal cortex. Furthermore, behavioral studies have found that phenethylamine hallucinogens induce head shakes when directly administered into the medial prefrontal cortex. The receptor(s) by which morphine suppresses head shakes induced by serotonin agonists have not been characterized. We administered mu-opioid receptor agonists and antagonists to adult male Sprague-Dawley rats prior to treatment with the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which is known to induce head shakes via 5-HT2A receptors. The suppressant action of the moderately selective mu-opioid receptor agonist, buprenorphine (ID50 approximately 0.005 mg/kg, i.p.; a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist) was blocked by naloxone and pretreatment with the irreversible mu-opioid receptor antagonist clocinnamox. Another mu-opioid receptor agonist fentanyl also suppressed DOI-induced head shakes. In contrast, a delta-opioid receptor agonist was without effect on DOI-induced head shakes. Thus, activation of mu-opioid receptors can suppress head shakes induced by hallucinogenic drugs.

Topics: Amphetamines; Animals; Behavior, Animal; Binding, Competitive; Buprenorphine; Cinnamates; Male; Morphine Derivatives; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Opioid, mu; Serotonin Receptor Agonists; Tremor

High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of mu-opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl < morphine < or = buprenorphine = nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2- to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7- and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine dose-response curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at mu-opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.

Topics: Algorithms; Analgesics, Opioid; Animals; Buprenorphine; Cinnamates; Discrimination, Psychological; Dose-Response Relationship, Drug; Fentanyl; Male; Morphine; Morphine Derivatives; Nalbuphine; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, mu

Buprenorphine and methoclocinnamox are partial micro-opioid receptor agonists with potential use in the treatment of opioid abuse. The ability of these drugs to suppress respiration as well as their ability to antagonize the respiratory suppressant effects of morphine and heroin were tested in rhesus monkeys. Frequency (f), minute volume (V(e)) tidal volume (V(t)) in monkeys breathing air or 5% CO(2) in air were recorded using a pressure-displacement plethysmograph. Buprenorphine (0.001-10 mg/kg) produced a dose-dependent decrease in respiratory parameters that plateaued at a dose of 1 mg/kg in both air and 5% CO(2). Methoclocinnamox (0. 032-1 mg/kg) also produced dose-dependent respiratory depression that plateaued at a dose of 0.3 mg/kg in air, and was directly related to dose in 5% CO(2). Respiratory suppression produced by buprenorphine 1 and 10 mg/kg lasted for 3 and 7 days, respectively, whereas the suppression produced by the largest dose of methoclocinnamox (1 mg/kg, the solubility limit) lasted less than 24 h. Buprenorphine and methoclocinnamox antagonized morphine- and heroin-induced respiratory depression, and this antagonist effect was observed concomitantly with, as well as following, the mu-opioid receptor agonist effects of buprenorphine and methoclocinnamox. The mu-opioid receptor antagonist effects of buprenorphine (10 mg/kg) and methoclocinnamox (1 mg/kg) lasted for 2 weeks. These results suggest that buprenorphine and methoclocinnamox have a wide margin of safety in clinical use and that these two compounds have a prolonged, insurmountable, mu-opioid receptor antagonist effect after the disappearance of their agonist effects.

Topics: Animals; Buprenorphine; Cinnamates; Drug Antagonism; Heroin; Macaca mulatta; Morphine; Morphine Derivatives; Narcotic Antagonists; Narcotics; Receptors, Opioid, mu; Respiration; Time Factors

The opioid agonists morphine, etorphine, buprenorphine and U50,488 were examined alone and in combination with the insurmountable opioid antagonist clocinnamox (C-CAM) in squirrel monkeys responding under a schedule of shock titration. In this procedure, shock intensity increased every 15 sec from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-sec shock period produced a 15-sec timeout, after which shock resumed at the next lower intensity. When given alone, each of these agonists increased the median intensity at which the monkeys maintained shock [median shock level (MSL)]. At the highest dose examined alone, each agonist produced maximal increases in MSL and, except buprenorphine, decreased response rates. C-CAM dose-dependently antagonized the effects of morphine, etorphine and buprenorphine on MSL. In the presence of the higher C-CAM doses, etorphine, morphine and buprenorphine did not produce maximal effects on MSL. The effects of U50,488 were not systematically altered when tested in combination with the highest C-CAM dose. In general, C-CAM was more potent and the duration of antagonism was slightly longer against buprenorphine than against morphine and etorphine. Quantitative analysis of these data according to an extended model of yielded the following apparent affinity and efficacy estimates, respectively: etorphine (0. 085 mg/kg, 117); morphine (49 mg/kg, 24) and buprenorphine (0.62 mg/kg, 7.1). Determination of the individual q values over time indicated that the receptor population recovers more quickly after C-CAM antagonism of etorphine than from C-CAM antagonism of either morphine or buprenorphine. These data suggest that C-CAM functions as a long-lasting antagonist of mu opioid agonist actions in a shock titration procedure and yields estimates of relative intrinsic efficacy with the rank order of etorphine > morphine > buprenorphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthetics, Combined; Animals; Antigens, CD; Buprenorphine; Cell Adhesion Molecules; Cinnamates; Etorphine; Glycoproteins; Male; Morphine; Morphine Derivatives; Narcotic Antagonists; Pain Measurement; Saimiri