Neurobiological basis of fever.

Fever is a coordinated endocrine, autonomic, and behavioral response organized by the brain in response to inflammatory stimuli. We examined the mechanism of the febrile response to intravenous lipopolysaccharide (LPS) in the rat. LPS caused activation of microglia and tissue macrophages in the meninges and along penetrating blood vessels. The microglia produce cytokines, such as tumor necrosis factor-alpha, and cyclooxygenase type 2. The latter produces prostaglandins, which may cross the blood-brain barrier. We found that inhibition of COX at the preoptic area prevented fever, whereas injection of PGE2 at this site produced fever. Either i.v. LPS or PGE2 into the preoptic area activated a specific set of pathways, including the ventromedial preoptic area, which we believe to be a key regulatory site, and the paraventricular nucleus, which we believe produces autonomic and endocrine responses that cause elevation of body temperature. We hypothesize that the pathway connecting these two sites involves a double inhibitory relay through temperature-sensitive GABAergic neurons in the hypothalamus. This pathway would essentially "turn up the thermostat" during a fever, causing an increase in body temperature via normal thermoregulatory pathways.