Systemic a-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release

Huang, Qin-Heng, Victor J. Hruby, and Jeffrey B. Tatro. Systemic a-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release. Am. J. Physiol. 275 (Regulatory Integrative Comp. Physiol. 44): R524–R530, 1998.— Systemically administered a-melanocyte-stimulating hormone (a-MSH) inhibits endotoxin (lipopolysaccharide; LPS)or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered a-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic a-MSH suppresses the LPSinduced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 μg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0–8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0–2 h) and IL-6 bioassay (0–8 h). a-MSH (100 μg/kg ip) completely prevented the onset of LPS-induced fever during the first 3–4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal a-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal a-MSH during the first 4 h after LPS but had no effect on a-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered a-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal a-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.