Structural modifications of pro-opiomelanocortin-derived peptides alter their behavioral effects markedly

Previous findings showed that pro-opiomelanocortin-containing neurons and endocrine cells synthesize multiple forms of beta-endorphin (beta E) and alpha-melanocyte-stimulating hormone (alpha-MSH), and that tissue specific post-translational processing of pro-opiomelanocortin can change ratios of the forms of secreted peptides. We therefore investigated the structure-activity requirements for behavioral interactions between beta E1-31 and alpha-MSH. Adult, male Sprague-Dawley rats received i.c.v. administrations of various dose combinations of alpha-MSH and beta E peptides, and behavioral activities were quantitated over a 55-min period. The results showed that both alpha-MSH and beta E1-31 produced dose-related increases in grooming behaviors. alpha-MSH also induced a stretching and yawning syndrome (SYS). beta E1-31 had no effect on SYS but did produce catatonia. BE1-31 inhibited both the grooming and SYS produced by alpha-MSH in a dose-related manner, and alpha-MSH potentiated beta E1-31-induced catatonia. Both N-terminal acetylation and C-terminal modification reduced the effects of beta E1-31 and reduced the inhibition by beta E1-31 of alpha-MSH-induced effects. Although the C-terminal fragments beta E28-31, beta E30-31 and beta E6-31 were devoid of behavioral effects when administered alone, all three peptides inhibited the effects of alpha-MSH on grooming and SYS markedly. Both beta E28-31 and beta E30-31 also inhibited the effects of beta E1-31 and beta E1-27. These results indicate that many of the behavioral actions of beta E1-31 reside in the N-terminus, and modulatory effects on alpha-MSH actions reside in the C-terminus.(ABSTRACT TRUNCATED AT 250 WORDS)