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Effects of U-50,488H on isolated atria from rats chronically treated with the kappa-opioid agonist, U-50,488H.

The present investigation was aimed at determining if chronic activation of kappa- or mu-opioid receptors induce development of tolerance and dependence to kappa-opioid agonists on the isolated left atria of the rat. Tolerance to a kappa-agonist (specific tolerance) was induced by chronic administration of U-50,488H, a selective kappa-agonist (15 mg kg(-1) i.p. twice a day for 4 days). The animals were rendered tolerant to morphine by subcutaneous implantation of morphine pellets (75 mg per pellet) for 7 days. 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. Preparations from morphine-treated rats were not tolerant to the selective kappa-agonist, that is, there was no cross-tolerance between mu- and kappa-agonists. Dependence to the kappa-agonist was tested by administration in the organ bath of Mr-2266 (preferential kappa-antagonist) or nor-binaltorphimine (nor-BNI; selective kappa-antagonist). The administration in the organ bath of the kappa-antagonists Mr-2266 or nor-BNI to preparations from U-50,488H-treated rats induced an increase in atrial force of contraction. In contrast, the administration of the kappa-antagonists to preparations from control rats induced a decrease in atrial force of contraction. These findings demonstrate that left atria from chronically U-50488H-treated rats exhibit tolerance to the negative inotropic effects of U-50,488H as well as opioid withdrawal after nor-BNI.