Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs


Prostaglandin E2 (PGE2) is postulated to be a central mediator of fever. It is generally believed that it is produced in the preoptic area of the anterior hypothalamus (POA) because, among other evidence, its level increases both in the third ventricle and in the POA in response to pyrogens. However, lately, the question has arisen whether PGE2 might, in fact, be formed outside of the brain substance and then penetrate it, in particular through the organum vasculosum laminae terminalis. If produced outside the brain substance, the peripheral blockade of its synthesis should prevent lipopolysaccharides (LPS)-induced fever, whereas the intracarotid infusion of PGE2 should produce an increase in core temperature (Tc) as well as in preoptic PGE2. To verify this hypothesis, continuous measurements of Tc and preoptic PGE2 levels were made in conscious guinea pigs administered the PGE2 synthase inhibitor, indomethacin (10 or 50 mg/kg, im) 30 min before S. enteritidis LPS (2 μg/kg, iv) or before PGE2 microdialyzed into the POA (1 μg/μl at 2μl/min for 2.5 h) and during PGE2 infused into a carotid artery (1 μg and 10 μg/μl at 2 μl/min for 1 h). LPS induced a biphasic 1.4°C fever that was consistently associated with an increase in the level of PGE2 in the POA. Indomethacin at 10 mg/kg attenuated the course of the LPS-induced fever and prevented the associated increase in preoptic PGE2 for 90 min after fover onset; thereafter, PGE2 was significantly reduced by comparison with controls. Indomethacin at 50 mg/kg completely abolished both the fever and the increased levels of PGE2 in the POA; the fever induced by PGE2 microdialyzed into the POA was not affected by indomethacin pretreatment. The intracarotid infusion of PGE2 produced Tc falls and no increase in preoptic PGE2 levels. The indomethacin-induced blockade of fever and inhibition of the associated increase in preoptic PGE2 levels further substaintiates the presumptive link between PGE2 in the POA and fever caused by LPS. The failure of exogenous PGE2 infusion to induce increases in Tc and preoptic PGE2 levels excludes the possibility that PGE2 formed outside of the brain penetrates the POA and induces fever. Thus, in guinea pigs, the PGE2 associated with LPS-induced fever may be synthesized in the POA.

Document Type





preoptic area, microdialysis, indomethacin, endotoxin, body temperature

Publication Date


Journal Title

Brain research bulletin