Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered alpha-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 (i.c.v.) injection of alpha-MSH on lipopolysaccharide (LPS, 30 microg/kg i.p.)-induced fever in rats, in the presence and absence of the selective MC4R antagonist HS014. Treatment with alpha-MSH (1 microg, i.c.v.) suppressed LPS-induced increases in core body temperature (Tc), 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 (Tsk). 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 microg) not only prevented, but reversed the effect of alpha-MSH (1 microg) on Tc, thus resulting in augmented LPS-induced fever. In afebrile rats, alpha-MSH infusion caused a modest transient increase in Tc that was blocked by coinjected HS014, but was not accompanied by altered Tsk. 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 alpha-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.

The central melanocortin system and fever.

Fever is a phylogenetically ancient response that is mounted upon exposure of the host to pathogens or inflammatory agents. Melanocortin agonists act centrally to inhibit fever by acting at receptors, including the melanocortin-4 receptor, which is prominently expressed in key hypothalamic thermoregulatory centers. Furthermore, endogenous melanocortins act centrally as physiological modulators of fever, recruited during the febrile response to restrain its intensity. Functionally, these actions lie at the interface between the anti-inflammatory effects of melanocortins, which involve suppression of the synthesis and actions of proinflammatory cytokines, and the central control of thermoregulation. Considering the extensive neuroanatomic and functional overlaps between central pathways and peripheral effectors involved in thermoregulation and energy balance, it is not surprising that melanocortins have been found to influence the metabolic economy profoundly in pathological as well as normal states. For example, despite suppressing endotoxin-induced fever, endogenous melanocortins appear to mediate the associated anorexia, a classic component of the "illness syndrome" accompanying acute infections, and promote a negative energy balance. The thermoregulatory actions of melanocortins are in several respects functionally opposed, and are remarkably dependent on physiological state, indicating that responsiveness to melanocortins is a physiologically modulated variable. Elucidating the anti-inflammatory and thermoregulatory roles of central melanocortin receptors during inflammatory states may lead to novel pharmacotherapeutic targets based on selective targeting of melanocortin receptor subtypes, for clinical benefit in human disease states involving neuroinflammatory components and metabolic wasting.

Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats.

Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects, the MC4R selective agonist MRLOB-0001 (CO-His-d-Phe-Arg-Trp-Dab-NH(2)) was administered intracerebroventricularly to rats treated with Escherichia coli lipopolysaccharide (LPS, 30 microg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did not lower core body temperature (T(c)) in afebrile rats but did suppress LPS-induced increases in T(c) and associated decreases in tail skin temperature (T(sk)), an indicator of vasomotor thermoeffector function. In contrast, systemic treatment with MRLOB-0001 (150 ng iv) did not produce similar antipyretic effects. Coadministration of the selective MC4R antagonist HS014 (1 microg icv) blocked the antipyretic effects of MRLOB-0001. HS014 alone (1 microg icv) had no significant effect on LPS-induced increases in T(c) or decreases in T(sk) and in afebrile rats had no significant effects on T(c) or T(sk). We conclude that pharmacological activation of central MC4R suppresses febrile increases in T(c) and that inhibition of heat conservation pathways may contribute to this effect. These findings suggest that the central MC4R may mediate the long-recognized antipyretic effects of centrally administered melanocortins.