Mode of action of endogenous opiate peptides

Abstract

AS THE culmination of a search for endogenous ligands of the opiate receptor1–4, the structures of two closely related pentapeptides, isolated from porcine (brain, with morphine-like properties in pharmacological tests, have been reported by Hughes et al.5 The amino acid sequences of the pentapeptides, termed methionine enkephalin and leucine enkephalin, are Tyr-Gly-Gly-Phe-Met (Met5-enkephalin) and Tyr-Gly-Gly-Phe-Leu (Leu5-enkephalin), respectively. They behave as highly potent opiates in the mouse vas deferens and guinea pig ileum assays5. In addition, animals tolerant to morphine are also tolerant to enkephalin6. The action of the pentapeptides in the guinea pig ileum5 and when injected intracerebrally or intracerebroventricularly7–9 is very short lived, perhaps because of proteolytic degradation. A related peptide, with longer chain length has been shown to have a long duration of action10. Morphine and other narcotics have been shown to bind to the opiate receptor11–13 and inhibit adenylate cyclase activity in homogenates of neuroblastoma × glioma hybrid cells14,15, to inhibit cyclic AMP accumulation in intact hybrid cells15,16 and in rat brain homogenates17. We have tested the effects of Met5- and Leu5-enkephalin on NG108-15 adenylate cyclase activity, and show here that endogenous opiate peptides are potent, receptor-mediated, inhibitors of adenylate cyclase of neuroblastoma × glioma hybrid cells.