Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever

Bacterial infection causes fever, an adaptive but potentially self- destructive response, in the host. Also activated are counterregulatory systems such as the pituitary-adrenal axis. Antipyretic roles have also been postulated for certain endogenous central neuropeptides, including the melanocortins (α-MSH-related peptides). To test the hypothesis that endogenous central melanocortins have antipyretic effects mediated by central melanocortin receptors (MCRs), we determined the effect of intracerebroventricular injection of a synthetic MCR antagonist, Ac-Nle⁴,c- [Asp⁵,DNal(2')⁷,Lys¹⁰]α-MSH(4-10)-NH₂ (SHU-9119) in endotoxin- 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, the major MCR subtypes expressed in brain, SHU-9119 showed no intrinsic agonism, but it inhibited α-MSH-induced cAMP accumulation (IC₅₀ = 0.48 ± 0.19 and 0.41 ± 0.28 nM, respectively) and [¹²⁶I]-[Nle⁴,DPhe⁷]-α-MSH binding (IC₅₀ = 1.0 ± 0.1 and 0.9 ± 0.3 nM, respectively). In vivo exogenous α-MSH (180 pmol) inhibited fever in rats when administered intracerebroventricularly 30 min after Escherichia coli lipopolysaccharide (LPS) (25 μg/kg, i.p.). When co-injected with α-MSH, SHU-9119 (168 pmol, i.c.v.) prevented the antipyretic action of exogenous α-MSH. In contrast, neither α-MSH nor SHU- 9119, alone or in combination, affected body temperatures in afebrile rats. In LPS-treated rats, intracerebroventricular injection of SHU-9119 significantly increased fever, whereas intravenous injection of the 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 central melanocortins exert an antipyretic influence during fever by acting on MCRs located within the brain, independent of any modulation of the activity of the pituitary- adrenal axis.