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-leve r drug-discrimination procedure. Enadoline produced a reliable discriminati ve stimulus that was reproduced by the kappa -selective agonists PD 117302, U 50,488, GR 89686A, (-)-spiradoline, ICI 204448, and EMD 61753, and by th e 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 mi xed-action opioids nalbuphine and nalorphine, or by the less active enantio mers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respective ly. The selective mu -opioid antagonist beta -funaltrexamine (10.0 mg/kg) d id not appreciably alter the dose-effect function for enadoline in any subj ect. However, the nonselective and kappa -selective opioid antagonists quad azocine (0.03-3.0 mg/kg) and nor-BNI (3-10 mg/kg), and the mixed-action opi oid nalbuphine (0.3-30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were lo ng-lasting and did not distinguish between drugs purported to act at differ ent kappa -receptor subtypes. The present results bolster the view that com mon discriminative stimulus effects of enadoline and other opioids are medi ated by kappa -agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine s upport the idea that it acts with low efficacy at kappa -opioid receptors.