Opioid peptide receptors and membrane biology.

The opioid peptides, beta-endorphin and the enkephalins, exhibit binding to brain tissue that is stereospecific, of high affinity, and saturable; from comparisons of the pharmacological potencies of a number of alkaloids with their abilities to displace peptide binding, it is concluded that peptide binding is probably relevant to pharmacological response for beta-endorphin, but not necessarily for enkephalins. The results of structure-activity studies indicate that both the (1-5) and a C-terminal sequence of the beta-endorphin molecule are necessary for both binding and pharmacological response, while pentapeptide conformation is related to enkephalin binding and pharmacological potency. The binding of opioid peptides possesses a brain regional distribution similar to that of alkaloids, with greatest enrichment in the striate, somewhat lesser amounts in the hypothalamus, thalamus, and amygdala, and least in the cortex and cerebellum; physiochemical properties, including inhibition by Na+, GTP, and by pretreatment of brain tissue with sulfhydryl reagents and proteolytic and lipolytic enzymes, are also similar to those of alkaloids. Other evidence, however, indicates that enkephalins and alkaloids bind to different sites: (1) differences in the abilities of enkephalins and alkaloids to displace labeled enkephalin and labeled alkaloid binding; (2) differences in relative pharmacological potencies of alkaloids and enkephalins in different systems; (3) small but significant differences in brain regional distribution and in certain physicochemical properties; and (4) selective protection of inhibition by irreversible reagents. This evidence, together with other data implicating both proteins and lipids in binding, has led us to propose a model of the beta-endorphin receptor in which the peptide binds to both an enkephalin site, located on a protein, and an alkaloid site, located on a lipid. Binding of enkephalins and beta-endorphin is related to a number of membrane-associated processes that are similarly affected by alkaloid binding, including changes in activity of adenylate cyclase and protein kinase, and in lipid metabolism and calcium ion disposition; some or all of these factors are presumably involved in the mediation of acute and chronic pharmacological effects. All of this work should be greatly aided by isolation of functionally active binding material, and recent work suggests that this breakthrough is finally possible.