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.