Kappa receptors mediate the peripheral aversive effects of opiates

Previous evidence has suggested that endogenous and exogenous opioids produce positive reinforcing effects through an action on central nervous system opiate receptors and aversive effects through an action on peripheral opiate receptors. In order to investigate the pharmacological specificity of the opiate aversive effects to peripheral opiate receptor subtypes, drug naive rats were administered various subcutaneous or intraperitoneal dose of the specific kappa receptor agonist U50,488 (0.005-16 mg/kg) and run in a place conditioning paradigm. The results were compared to previously published data on the motivational effects of morphine, collected using identical experimental procedures. Regardless of the route of administration, the majority of doses of U50,488 produced conditioned place aversions, whereas increasing doses of morphine produced conditioned place preferences. Only a low dose of morphine (0.05 mg/kg intraperitoneally but not subcutaneously) was shown to produce significant place aversions, suggesting a local gut effect. Vagotomy blocked the aversive properties of morphine, and in the present report shifted the motivational effects of moderate doses of U50,488 into preferences. U50,488 produced aversions at a dose that was 5 times lower than the low dose of morphine that produced aversive effects. Even at very high doses, U50,488 did not produce the conditioned place preferences seen with morphine. These high dose aversions induced by U50,488 were attenuated by a low intraperitoneal dose of the kappa antagonist Mr2266. In order to investigate the possible actions of peripheral, endogenous kappa agonists, a dose-response curve was generated in the place conditioning paradigm from separate groups of naive rats injected with various intraperitoneal doses of the specific kappa antagonist Mr2266 (0.001-10 mg/kg) or its inactive isomer Mr2267 (0.01-10 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)