Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists.
The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine failed to antagonize dezocine's rate-decreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors.
Picker
M J
MJ
Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010856:Columbidae; D003516:Cycloparaffins / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D005260:Female; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013764:Tetrahydronaphthalenes
D000701:Analgesics, Opioid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003516:Cycloparaffins; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013764:Tetrahydronaphthalenes; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; C010827:dezocine