STRUCTURAL MODIFICATIONS OF PRO-OPIOMELANOCORTIN-DERIVED PEPTIDES ALTER THEIR BEHAVIORAL-EFFECTS MARKEDLY

Abstract

Previous findings showed that pro-opiomelanocortin-containing neurons and endocrine cells synthesize multiple forms of beta-encorphin (.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. It is proposed that selective biosynthetic processing of pro-opiomelanocortin in regions of rat brain may influence the functional consequences of the secreted pepitdes.