nalorphine and beta-funaltrexamine

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Topics: Animals; Buprenorphine; Butorphanol; Columbidae; Discrimination Learning; Female; Fentanyl; Levallorphan; Methadone; Morphine; Nalbuphine; Nalorphine; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu

Systemic administration of beta-funaltrexamine (beta-FNA) 24 hr before analgesic testing produced approximately a 10-fold parallel shift in the dose-response curves of the prototypic mu agonists morphine, I-methadone, fentanyl and etorphine in the mouse abdominal constriction test. In contrast, prior administration of beta-FNA produced no appreciable shift in the analgesic dose-response curve of the selective kappa agonist, U-50, 488H. These results suggest that beta-FNA is selective for mu over kappa receptors under the conditions used in this study. The dose-response curves for ethylketazocine and proxorphan were affected only to a small extent by beta-FNA pretreatment, suggesting that these compounds have analgesic actions mediated primarily through nonmu, probably kappa receptors. The dose-response curves for cyclazocine, buprenorphine, butorphanol, nalorphine and nalbuphine were shifted markedly to the right and frequently not in a parallel fashion by the prior administration of beta-FNA. These results seem to indicate a major role for the mu receptor in the analgesic actions of these compounds.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Animals; Biological Assay; Buprenorphine; Butorphanol; Cyclazocine; Dose-Response Relationship, Drug; Ethylketocyclazocine; Etorphine; Fentanyl; Methadone; Mice; Morphine; Muscle Contraction; Nalbuphine; Nalorphine; Naltrexone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, mu

Previous studies have demonstrated that pretreatment of guinea pig longitudinal muscle-myenteric plexus ileal preparations with the highly selective noncompetitive mu antagonist beta-funaltrexamine (beta-FNA) causes an increase in the Ke value for the interaction of morphine with naloxone, suggesting that beta-FNA inactivates those receptors at which morphine interacts in the guinea pig ileum. The effect is selective for mu receptors since beta-FNA has no effect upon the interaction of naloxone with the kappa agonist nalorphine. In the present study, it was found that although beta-FNA attenuated the effects of morphine and other morphine-like agonists at mu receptors in the guinea pig longitudinal muscle-myenteric plexus ileal preparation, the mu-mediated actions of delta-selective peptide agonists and mu-selective peptide agonists were not completely attenuated by beta-FNA pretreatment. These data suggest that morphine-like mu agonists and other mu-selective and delta-selective peptide agonists in the guinea-pig ileum preparation either interact with similar opioid receptors but in a distinguishable manner or interact with different populations of opioid receptors or the peptides studied had greater intrinsic activity than the nonpeptides.

Topics: Animals; Endorphins; Guinea Pigs; Ileum; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Nalorphine; Naloxone; Naltrexone; Narcotics; Peptides; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship

Topics: Animals; Binding Sites; Kinetics; Naltrexone; Narcotic Antagonists; Narcotics; Receptors, Opioid; Structure-Activity Relationship

Topics: Animals; Charcoal; Cyclazocine; Drug Interactions; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethylketocyclazocine; Female; Gastrointestinal Motility; Male; Mice; Morphine; Nalorphine; Naltrexone; Receptors, Opioid

The profile of action of beta-funaltrexamine (beta-FNA), the fumaramate methyl ester derivative of naltrexone, on antinociceptive tests in vivo was investigated. Beta-FNA demonstrated antinociceptive actions that were of short duration and that appeared to be mediated by kappa receptor interaction. In contrast, the antagonist actions of beta-FNA were of remarkably long duration and were selective toward nu agonist interactions. This profile of action is consistent with the profile of action of beta-FNA in vitro. The selective long-lasting antagonism of mu-mediated effects by beta-FNA may be of great value in the elucidation of multiple opioid receptor function.

Topics: Acetates; Acetic Acid; Analgesics, Opioid; Animals; Drug Interactions; Female; Male; Mice; Morphine; Nalorphine; Naloxone; Naltrexone; Narcotics; Pain; Reaction Time