VENTROMEDIAL PREOPTIC PROSTAGLANDIN-E2 ACTIVATES FEVER-PRODUCING AUTONOMIC PATHWAYS

Fever is thought to be initiated by pyrogenic cytokines inducing the p roduction of prostaglandin E2 (PGE2) in the preoptic area (POA); PGE2 may act as a paracrine mediator that stimulates the neural pathways th at raise body temperature. This essential role for prostaglandins in f ever first was proposed 25 years ago, but the specific preoptic cell g roups at which PGE2 acts and the pathways through which fever is produ ced remain poorly understood. To better define the role of preoptic PG E2 in fever, we developed a new method for combining acute brain injec tions with Fos immunohistochemistry. We microinjected a threshold dose of PGE2 to construct an anatomically detailed map of fever-producing preoptic sites. The most pyrogenic preoptic sites were clustered along the ventromedial aspect of the POA, surrounding and just anterior to the organum vasculosum of the lamina terminalis. We then used Fos immu nohistochemistry to identify the pattern of neural activation induced by fever-producing preoptic injections of PGE2 and compared it with th e Fos pattern seen after systemic immune stimulation. PGE2 fever was a ccompanied by Fos induction in the ventromedial POA and the parvicellu lar subnuclei of the paraventricular nucleus of the hypothalamus (PVH) . In contrast to the Fos pattern seen after intravenous lipopolysaccha ride administration, PGE2 injection did not induce Fos in the circumve ntricular organs or the magnocellular subnuclei of the PVH. These obse rvations establish a potential site of PGE2 action during fever and he lp define candidate pathways through which fever occurs.