Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered α-MSH

Activation of central melanocortin receptors (MCR) inhibits fever but can also stimulate thermogenesis, and the mechanisms involved are unknown. To determine whether the long-recognized antipyretic effect of exogenous alpha-MSH is mediated by the melanocortin-4 receptor (MC4R), and what thermoeffector systems are involved, we tested the effects of intracerebroventricular (icv) injection of alpha-MSH on lipopolysaccharide (LPS, 30 mug/kg ip)-induced fever in rats, in the presence and absence of the selective MC4R antagonist HS014. Treatment with a-MSH (1 mug, icv) suppressed LPS-induced increases in core body temperature (T,), whereas a lower dose (300 ng) was ineffective. Nevertheless, both alpha-MSH doses effectively inhibited LPS-induced peripheral vasoconstriction, the principal heat-conserving thermoeffector, as determined by changes in tail skin temperature (T-sk). This implies that the net antipyretic effect of alpha-MSH cannot be accounted for solely by modulation of heat loss effectors, but also involves other mechanisms. Surprisingly, central MC4-R blockade by coinjected HS014 (1 mug) not only prevented, but reversed the effect of alpha-MSH (1 mug) on T-c, thus resulting in augmented LPS-induced fever. In afebrile rats, alpha-MSH infusion caused a modest transient increase in T-c that was blocked by coinjected HS014, but was not accompanied by altered T-sk. Overall, the results support the hypothesis that the MC4R mediates the antipyretic effects of alpha-MSH. Paradoxically, in the presence of pharmacological MC4-R blockade during fever, exogenous a-MSH can exacerbate fever, probably by acting via other central MCR subtype(s). In normal animals, centrally injected alpha-MSH exerts a hyperthermic effect that is mediated by the MC4R, consistent with recent evidence that MC4R activation promotes energy expenditure in normal states through stimulation of thermogenesis. (C) 2004 Elsevier B.V. All rights reserved.