BOTH DYNORPHIN A(1-17) AND [DES-TYR(1)]DYNORPHIN A(2-17) INHIBIT ADENYLYL-CYCLASE ACTIVITY IN RAT CAUDATE-PUTAMEN

In this study, the ability of a series of dynorphin peptides to inhibi t adenylyl cyclase (AC) activity was determined. The endogenous ligand of the kappa opioid receptor, dynorphin A(1-17) (Dyn A(1-17)), produc ed a significant concentration-dependent inhibition of AC activity in membranes prepared from the caudate putamen (CPu) of naive Fischer 344 rats. The opioid receptor antagonist, naloxone (10(-5) M), which is p redominantly mu opioid receptor directed, but with modest kappa and de lta receptor activity, partially blocked this inhibition. Nor-Binaltor phimmine (10(-5) M), the selective kappa receptor antagonist, also blo cked the effect of Dyn A(1-17), but to a lesser degree. [Des-Tyr(1)]Dy n A(2-17), a major nonopioid biotransformation product of Dyn A(1-17) with known biological activities, also inhibited AC in rat CPu membran es. Dyn A(1-13) inhibited AC, as did its major opioid biotransformatio n product, Dyn A(1-12). One of the major nonopioid biotransformation p roducts of Dyn A(1-13), Dyn A(4-12), showed no activity. Dyn A(2-12), another nonopioid product of Dyn A(1-13), showed limited activity. Dyn A(1-6), a minor biotransformation product of both Dyn A(1-17) and Dyn A(1-13), also inhibited AC activity. These findings suggest that, in rat CPu membranes, the inhibition of AC activity by Dyn A(1-17) is med iated in part by kappa and mu opioid receptors. In addition, Dyn A(2-1 7), and to a lesser extent Dyn A(2-12), may bind to a yet unidentified site that is also coupled to the AC enzyme in rat CPu.