Role of central melanocortins in endotoxin-induced anorexia

Inflammation and microbial infection produce symptoms, including fever, ano rexia, and hypoactivity, that are thought to be mediated by endogenous proi nflammatory cytokines. Melanocortins are known to act centrally to suppress effects on fever and other sequelae of proinflammatory cytokine actions in the central nervous system, but the roles of melanocortins in anorexia and hypoactivity occurring during the acute phase response are unknown. The pr esent study was designed to determine the effects of exogenous and endogeno us alpha-melanocyte stimulating hormone (alpha-MSH) on lipopolysaccharide ( LPS)-induced anorexia in relation to their effects on fever. Rats were fast ed overnight to promote feeding behavior, then injected intraperitoneally w ith LPS (100 mu g/kg ip), followed 30 min later by intracerebroventricular injection of either alpha-MSH or the melanocortin receptor subtype 3/subtyp e 4 (MC3-R/MC4-R) antagonist SHU-9119. Food intake, locomotor activity, and body temperature (T-b) were monitored during the ensuing 24-h period. Each of two intracerebroventricular doses of alpha-MSH (30 and 300 ng) potentia ted the suppressive effects of LPS on food intake and locomotion, despite t he fact that the higher dose alleviated LPS-induced fever. In control rats that were not treated with LPS, only the higher dose of alpha-MSH significa ntly inhibited food intake, and T-b and locomotor activity were unaffected. To assess the roles of endogenous central melanocortins, LPS-treated rats received intracerebroventricular SHU-9119 (200 ng). Central MC3-R/MC4-R blo ckade did not affect Tb or food intake in the absence of LPS treatment, but it reversed the LPS-induced reduction in 24-h food intake and increased LP S-induced fever without altering the LPS-induced suppression of locomotion. Taken together, the results suggest that exogenous and endogenous melanoco rtins acting centrally exert divergent influences on different aspects of t he acute phase response, suppressing LPS-induced fever but contributing to LPS-induced anorexia and hypoactivity.