Endogenous antipyretics

Fever is the hallmark of the stereotyped host response to microbial infecti on, although it is just one of a number of high-risk strategies employed by the infected host to clear itself of invading pathogens. The febrile respo nse is accompanied by activation of multiple endogenous antipyretic systems that serve to suppress its magnitude or duration. These include neuroactiv e substances of neural and humoral origin, some of which (e.g., glucocortic oids, melanocortins, and IL-IO) have broad-ranging anti-inflammatory action s. Glucocorticoids, vasopressin, and melanocortins appear to exert their an tipyretic effects by acting on receptors within the brain, but beyond this the mechanisms involved are unknown. It is hypothesized, but not proven, th at endogenous antipyretic systems protect the host against the destructive consequences of unchecked fever. Importantly, pharmacological blockade of t he actions of endogenous antipyretic systems increases fevers of even low t o moderate intensity. Therefore, in addition to protecting against catastro phic consequences of high fever, endogenous antipyretic systems seem to pla y a fundamental physiological role in determining the normal course of feve r. Elucidating the neural and biochemical mechanisms involved in suppressio n of fever by physiological antipyretic systems will yield a rich benefit, both by advancing the basic understanding of host defense strategies, and b y permitting the design of novel antipyretic and antiinflammatory strategie s for therapeutic intervention in human disease.