Behavioral effects of a novel kappa opioid analgesic, U-50488, in rats and rhesus monkeys.

U-50488 [trans-3,4-dichloro-N-(2-(1-pyrrolidinyl) cyclohexyl)-benzeneacetamide] is a structurally novel analgesic reported to have specific kappa opioid receptor agonist properties. Potent antinociceptive activity was demonstrated in rhesus monkeys and the effect was reversed by naloxone. The overt behavioral effects of U-50488 at supra-analgesic doses more closely resembled those of ethylketocyclazocine (EKC) than morphine. In monkeys trained to discriminate a 10-micrograms/kg dose of EKC from saline, the stimulus effects generalized completely to U-50488 and other kappa agonists (e.g., bremazocine, cyclazocine), but not to the pure mu agonists. Like the other kappa agonists, U-50488 produced diuresis in monkeys by a naloxone-sensitive mechanism. In drug-naive rats offered continuous opportunity to self-administer drugs IV, most rats self-administered morphine or EKC, but none of the rats self-administered U-50488 at a rate above that of a group offered saline. Rats with continuous IV infusion of U-50488 for 3 weeks exhibited few abstinence signs and no weight loss when challenged with an injection of naloxone or after abrupt cessation of drug infusion. These experimental results support the previous reports in mice that U-50488 is a very selective kappa opioid agonist in rats and rhesus monkeys.