Hypothalamic prostaglandin E(2) during lipopolysaccharide-induced fever in guinea pigs

Prostaglandin E(2) (PGE(2)) 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 PGE(2) might, in fact, be formed outside of the brain substance and then penetrate it, in particular through the organum vascolosum laminae terminal. If produced outside the brain substance, the peripheral blockade of its synthesis should prevent lipopolysaccharides (LPS)-induced fever, whereas the intracarotid infusion of PGE(2) should produce an increase in core temperature (T-c) as well as in preoptic PGE(2). To verify this hypothesis, continuous measurements of T-c and preoptic PGE(2) levels were made in conscious guinea pigs administered the PGE(2) synthase inhibitor, indomethacin (10 or 50 mg/kg, im) 30 min before S. enteritidis LPS (2 mu g/kg, iv) or before PGE(2) microdialyzed into the POA (1 mu g/mu l at 2 mu l/min for 2.5 h) and during PGE(2) infused into a carotid artery (1 pg and 10 mu g/mu l at 2 mu l/min for 1 h). LPS induced a biphasic 1.4 degrees C fever that was consistently associated with an increase in the level of PGE(2) in the POA. Indomethacin at 10 mg/kg attenuated the course of the LPS-induced fever and prevented the associated increase in preoptic PGE(2) for 90 min after fever onset; thereafter, PGE(2) was significantly reduced by comparison with controls. Indomethacin at 50 mg/kg completely abolished both the fever and the increased levels of PGE(2) in the POA; the fever induced by PGE(2) microdialyzed into the POA was not affected by indomethacin pretreatment. The intracarotid infusion of PGE(2) produced T-c falls and no increase in preoptic PGE(2) levels. The indomethacin-induced blockade of fever and inhibition of the associated increase in preoptic PGE(2) levels further substantiates the presumptive link between PGE(2) in the POA and fever caused by LPS. The failure of exogenous PGE(2) infusion to induce increases in T-c and preoptic PGE(2) levels excludes the possibility that PGE(2) formed outside of the brain penetrates the POA and induces fever. Thus, in guinea pigs, the PGE(2) associated with LPS-induced fever may be synthesized in the POA.