Enadoline discrimination in squirrel monkeys: effects of opioid agonists and antagonists.
Squirrel monkeys were trained to discriminate i.m. injections of the kappa-opioid receptor agonist enadoline (0.0017 mg/kg) from saline in a two-lever drug-discrimination procedure. Enadoline produced a reliable discriminative stimulus that was reproduced by the kappa-selective agonists PD 117302, U 50,488, GR 89686A, (-)-spiradoline, ICI 204448, and EMD 61753, and by the mixed-action kappa/mu-agonists bremazocine and ethylketocyclazocine. The discriminative stimulus effects of enadoline were not reproduced by the mu-selective agonist morphine, the delta-selective agonist BW373U86, the mixed-action opioids nalbuphine and nalorphine, or by the less active enantiomers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respectively. The selective mu-opioid antagonist beta-funaltrexamine (10.0 mg/kg) did not appreciably alter the dose-effect function for enadoline in any subject. However, the nonselective and kappa-selective opioid antagonists quadazocine (0.03-3.0 mg/kg) and nor-BNI (3-10 mg/kg), and the mixed-action opioid nalbuphine (0.3-30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were long-lasting and did not distinguish between drugs purported to act at different kappa-receptor subtypes. The present results bolster the view that common discriminative stimulus effects of enadoline and other opioids are mediated by kappa-agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine support the idea that it acts with low efficacy at kappa-opioid receptors.
Carey
G J
GJ
Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
Bergman
J
J
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009266:Nalbuphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology; D012453:Saimiri; D013876:Thiophenes / Q000494:pharmacology
D001572:Benzofurans; D009292:Narcotic Antagonists; D011758:Pyrroles; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013876:Thiophenes; C054718:PD 117302; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine; C067110:enadoline; D009266:Nalbuphine