ANTIPYRETIC ROLE OF ENDOGENOUS MELANOCORTINS MEDIATED BY CENTRAL MELANOCORTIN RECEPTORS DURING ENDOTOXIN-INDUCED FEVER

Bacterial infection causes fever, an adaptive but potentially self-des tructive response, in the host. Also activated are counterregulatory s ystems such as the pituitary-adrenal axis. Antipyretic roles have also been postulated for certain endogenous central neuropeptides, includi ng the melanocortins (alpha-MSH-related peptides). To test the hypothe sis that endogenous central melanocortins have antipyretic effects med iated by central melanocortin receptors (MCRs), we determined the effe ct of intracerebroventricular injection of a synthetic MCR antagonist, ,c-[Asp(5),DNal(2')(7),Lys(10)]alpha-MSH(4-10)-NH2 (SHU-9119) in endo toxin-challenged rats. The efficacy and specificity of SHU-9119 as an MCR antagonist in the rat was first validated in vitro and in vivo. In vitro, in heterologous cells expressing either rat MC3-R or MC4-R, th e major MCR subtypes expressed in brain, SHU-9119 showed no intrinsic agonism, but it inhibited alpha-MSH-induced cAMP accumulation (IC50 = 0.48 +/- 0.19 and 0.41 +/- 0.28 nM, respectively) and [I-125]-[Nle(4), Dphe(7)]alpha-MSH binding (IC50 = 1.0 +/- 0.1 and 0.9 +/- 0.3 nM, resp ectively). In vivo, exogenous alpha-MSH (180 pmol) inhibited fever in rats when administered intracerebroventricularly 30 min after Escheric hia coil lipopolysaccharide (LPS) (25 mu g/kg, i.p.). When co-injected with alpha-MSH, SHU-9119 (168 pmol, i.c.v.) prevented the antipyretic action of exogenous alpha-MSH. In contrast, neither alpha-MSH nor SHU -9119, alone or in combination, affected body temperatures in afebrile rats. In LPS-treated rats, intracerebroventricular injection of SHU-9 119 significantly increased fever, whereas intravenous injection of th e same dose of SHU-9119 had no effect. Neither intracerebroventricular nor intravenous SHU-9119 significantly affected LPS-stimulated plasma ACTH or corticosterone levels. The results indicate that endogenous c entral melanocortins exert an antipyretic influence during fever by ac ting on M6Rs located within the brain, independent of any modulation o f the activity of the pituitary-adrenal axis.