Effects of chronic U-50,488H treatment on the isolated right atrium of the rat.

The aim of the present investigation was to determine if chronic activation of kappa-opioid receptor induces development of tolerance and dependence to kappa-opioid agonists on the isolated right atrium of the rat. Tolerance to the kappa-agonist was induced by chronic administration of U-50,488H, a selective kappa-agonist (15 mg/kg i.p. twice a day for 4 days). The rats were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve; it was accompanied by a decrease in the maximum response and in the slope. Withdrawal to the kappa-agonist was induced by administration of Mr-2266 (preferentially kappa-antagonist) or nor-binaltorphimine (nor-bni; selective kappa-antagonist) to the organ bath. The administration of the kappa-antagonists Mr-2266 or nor-bni to preparations from tolerant rats in the organ bath induced an increase in auricular contraction frequency. In contrast, the administration of the kappa-antagonists to preparations from vehicle-treated rats induced a decrease in auricular contraction frequency. These findings demonstrate that the hearts of rats that had received chronic U-50,488H treatment develop tolerance to the cardiac effects of U-50,488H and exhibit excitatory reactions to kappa-antagonist's precipitated withdrawal.