The selective kappa-opioid receptor agonist U50,488H attenuates voluntary ethanol intake in the rat

Non-selective opioid receptor antagonists are increasingly used in the trea tment of alcohol dependence. The clinical effects are significant but the e ffect size is rather small and unpleasant side effects may limit the benefi ts of the compounds. Ligands acting at mu- and or delta- receptors can alte r the voluntary intake of ethanol in various animal models. Therefore, the attenuating effects of selective opioid receptor ligands on ethanol intake may be of clinical interest in the treatment of alcoholism. The objective o f this study was to examine the effects of a selective K-receptor agonist, U50,488H on voluntary ethanol intake in the rat. We used a restricted acces s model with a free choice between an ethanol solution (10%, v/v) and water . During the 3-days baseline period, the rats received a daily saline injec tion (1 ml/kg, i.p.) 15 min before the 2 h access to ethanol. The animals h ad free access to water at all times. The control group received a daily sa line injection during the 4-days treatment-period, whereas the treatment gr oups received a daily dose of U50,488H (2.5, 5.0 or 10 mg/kg per day). Anim als treated with U50,488H dose-dependently decreased their ethanol intake. The effect of the highest dose of U50,488H was reduced by pre-treatment wit h the selective tc-antagonist nor-binaltorphimine (nor-BNI). These results demonstrate that activation of kappa -opioid receptors can attenuate volunt ary ethanol intake in the rat, and the data suggest that the brain dynorphi n/kappa -receptor systems may represent a novel target for pharmacotherapy in the treatment of alcohol dependence. (C) 2001 Elsevier Science B.V. All rights reserved.