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 activ ation of kappa-opioid receptor induces development of tolerance and de pendence to kappa-opioid agonists on the isolated right atrium of the rat. Tolerance to the kappa-agonist was induced by chronic administrat ion 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 wa s observed after its chronic administration and was revealed as a righ tward shift of the concentration-response curve; it was accompanied by a decrease in the maximum response and in the slope, Withdrawal to th e kappa-agonist was induced by administration of Mr-2266 (preferential ly kappa-antagonist) or nor-binaltorphimine (nor-bni; selective kappa- antagonist) to the organ bath. The administration of the kappa-antagon ists Mr-2266 or nor-bni to preparations from tolerant rats in the orga n bath induced an increase in auricular contraction frequency, In cont rast, the administration of the kappa-antagonists to preparations from vehicle-treated rats induced a decrease in auricular contraction freq uency. These findings demonstrate that the hearts of rats that had rec eived chronic U-50488H treatment develop tolerance to the cardiac effe cts of U-50,488H and exhibit excitatory reactions to kappa-antagonist' s precipitated withdrawal.