Selective Tolerance at Mu and Kappa Opioid Receptors Modulating Norepinephrine Release in Guinea Pig Cortex

The development of selective tolerance, that is, a loss in the ability of an agonist to exert an effect without concomitant loss in the ability of an agonist which acts through another receptor type to similarly lose its effectiveness, has provided supporting evidence for the existence of multiple opioid receptor types in brain and peripheral tissues. In brain, this phenomenon has generally been demonstrated for agonists which produce different physiological effects. In this study, we describe selective tolerance at two opioid receptor types which converge upon a single function. The effects of chronic treatment for 6 days with the mu agonist morphine (1.7 mg/kg/hr) and the kappa agonist U50, 488H (300 micrograms/kg/hr) on the ability of mu and kappa opioid agonists to inhibit the stimulated release of [3H]norepinephrine from slices of guinea pig cortex were investigated. Mu, delta and kappa selective agonists have been shown previously to be capable of regulating the stimulated release of norepinephrine. Chronic administration of morphine resulted in a diminution in the ability of the mu agonists Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol, morphine and etorphine, but not of U50, 488H, to inhibit the stimulated release of [3H]norepinephrine. Conversely, chronic U50, 488H infusion decreased the ability of U50, 488H to inhibit release, with no change in the effectiveness of Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol. The degree of tolerance observed for mu agonists in tissue from morphinized animals is discussed with regard to their efficacy and selectivity.