Aversive Effects of the Kappa Opioid Agonist U‐50488 Alone and in Combination with the Cannabinoid Agonist CP 55,940 in Male Rats

Abstract

Kappa (κ) opioid receptor agonists can produce prominent analgesic and diuretic effects when administered alone and these effects can be enhanced by the co‐administration of cannabinoids such as CP 55,940. The purpose of the present experiment was to determine if cannabinoids can also enhance the aversive effects of kappa agonists, because these effects substantially reduce their clinical utility as analgesics and aquaretics. To study the aversive effects of kappa agonists and their interaction with cannabinoids, nine male Long‐Evans rats were trained to respond for food under a fixed‐ratio (FR) schedule of food presentation and then implanted with intravenous (i.v.) catheters. Following recovery, the subjects were transitioned to a multiple FR, FR schedule. More specifically, in the presence of a single white stimulus light, food was presented under a fixed‐ratio 30 (FR‐30) schedule (non‐infusion component), whereas presence of both this white stimulus light and a green stimulus light, an i.v. infusion was presented on the first response of each FR and food was presented on the thirtieth FR response (infusion component). When responding was consistent in both components, varying infusion doses of U‐50488 (0.032 – 0.18 mg/kg) replaced the baseline saline infusion until one of three criterion was met: 3 days in which the variability of responding did not vary by ± 20% of the mean, 3 days of responding at less than 0.3 responses per sec, or a maximum of 8 days. After the criterion was met for each dose substitution, the subjects returned to the baseline in which saline served as the infusion and responding was similar between components. To study the interaction of CP 55,940 with the effects of U‐50488, single acute injections of a dose of CP 55,940 (0.056 mg/kg) were administered prior to sessions in which a dose of U‐50488 was available in the infusion component. Each dose‐infusion combination was administered until subjects met the criterion. These effects were then compared to sessions in which one of two doses of naltrexone (1, 3.2 mg/kg) was administered prior the same U‐50488 infusion doses. When infusions of U‐50488 replaced saline, low infusion doses (e.g., 0.056 mg/kg/infusion) selectively suppressed responding in the infusion component, while higher infusion doses (e.g., 0.18 mg/kg/infusion) decreased responding in both components as the total dose of U‐50488 for the session increased. Administration of CP 55,940 did not produce a marked enhancement of the suppressive effects of U‐50488 at the dose tested, and surprisingly, neither dose of naltrexone antagonized its suppressive effects. Together, these data demonstrate the aversive effects of U‐50488 alone, the absence of a marked enhancement by at least one cannabinoid agonist, and the surprising absence of antagonism by the opioid receptor antagonist naltrexone.