Proinflammatory cytokines induced by microbial infection and inflammatory stimuli activate major autonomic and neuroendocrine responses within the CNS, including fever and stimulation of the pituitary-adrenal (HPA) axis. Melanocortins inhibit diverse proinflammatory cytokine actions, in part by acting act via melanocortin receptors (MCR) within the CNS, but the mechanisms are unknown. The long-term objectives of this proposal are to determine the central pathways involved, and the roles of specific MCR subtypes, in mediating melanocortin-induced inhibition of endotoxin (LPS) and interleukin-1 (IL1) actions in the brain; and the role of hypothalamic neurons producing a novel endogenous MCR antagonist (agouti-related protein; AgRP) in determining central autonomic and thermoregulatory responses to inflammatory stimuli. Three hypotheses will be tested: 1) that melanocortins act via the central MC3-R and MC4-R to counteract a delayed hypothermic influence of IL1, by activating sympathetically-controlled thermoeffectors; 2) that endogenous AgRP produced in hypothalamic neurons regulates central responsiveness to melanocortin effects on IL1-induced thermogenesis and pituitary-adrenal responses; and 3) that alpha- MSH-induced suppression of the LPS-induced febrile response may involve inhibition of NFkB activation and cyclooxygenase-2 (COX- 2) expression. The specific aims are: 1) to determine the influence of the central MC3 and MC4 receptor subtypes on the functions of sympathetically-driven thermoeffectors involved in thermogenesis and heat conservation during the early (febrile) and late (hypothermic) phases of the response to central IL1; 2) to determine whether AgRP produced in hypothalamic neurons acts as a physiological inhibitor of the suppressive influence of CNS melanocortins on LPS- and IL1-induced fever and HPA activation; 3) to determine whether melanocortins inhibit LPS-induced fever and HPA activation by acting within the ventromedial preoptic region; and 4) to determine whether alpha-MSH acts centrally to suppress LPS- induced NFkB activation and/or COX-2, and to determine the localization of these effects in relation to the distribution of R-MC4-R-, and MC5-R- expressing cells in the ventromedial preoptic region and ventrolateral medulla. Endogenous central melanocortins may protect against the potentially destructive effects of cytokines during infection, including cytokine-driven HIV replication in the CNS. With a more sophisticated knowledge of the complex CNS signaling pathways engaged by melanocortins, therapeutic strategies based on selective targeting of MCR subtypes in the CNS may offer clinical benefit in infectious and autoimmune disease.