RELATIONSHIP BETWEEN KAPPA(1)-OPIOID RECEPTOR-BINDING AND INHIBITION OF ADENYLYL CYCLASE IN GUINEA-PIG BRAIN MEMBRANES

Previously, we showed that kappa-selective ligands inhibit adenylyl cyclase in guinea pig cerebellar membranes. The present studies explore the relationship between kappa1 binding sites (as determined with [H-3]U-69,593 binding) and kappa1-inhibition of adenylyl cyclase (using U-50,488H) in guinea pig brain membranes. VarioUS kappa Opioids displaced [H-3]U-69,593 binding at a single site with subnanomolar affinities. These agonists were several hundred-fold weaker in inhibiting adenylyl cyclase, but for most agonists the rank order of adenylyl cyclase inhibition paralleled the displacement of kappa1 binding. The correlation of IC50 values for both adenylyl cyclase and binding was significant except for alpha-neo endorphin, which was relatively weak at inhibiting adenylyl cyclase despite a K(i) value of 0.08 nM versus kappa1 binding. Comparison between kappa1 binding and kappa1-inhibited adenylyl cyclase across eleven guinea pig brain regions revealed that kappa1-inhibited adenylyl cyclase was highest in the cerebellum, absent in thalamus and superior colliculus, and moderate in other regions. In most regions, kappa1 binding correlated with the efficacy of kappa1-inhibited adenylyl cyclase. However, the hippocampus had high levels of kappa1-inhibited adenylyl cyclase despite low levels Of kappa1 binding, while cortex exhibited a high density of kappa1 sites but a relatively low level of kappa1-inhibited adenylyl cyclase. Reaction of cerebellar kappa1 receptors with beta-chlornaltrexamine (beta-CNA) blocked both kappa1 binding and kappa1-inhibited adenylyl cyclase. The effect of beta-CNA on kappa1-inhibited adenylyl cyclase was to inhibit efficacy with little decrease in agonist potency, thus suggesting no significant level Of kappa receptor reserve for this effector system.