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 ar ea of the anterior hypothalamus (POA) because, among other evidence, i ts level increases both in the third ventricle and in the POA in respo nse to pyrogens. However, lately, the question has arisen whether PGE( 2) might, in fact, be formed outside of the brain substance and then p enetrate it, in particular through the organum vascolosum laminae term inal. If produced outside the brain substance, the peripheral blockade of its synthesis should prevent lipopolysaccharides (LPS)-induced fev er, whereas the intracarotid infusion of PGE(2) should produce an incr ease in core temperature (T-c) as well as in preoptic PGE(2). To verif y this hypothesis, continuous measurements of T-c and preoptic PGE(2) levels were made in conscious guinea pigs administered the PGE(2) synt hase inhibitor, indomethacin (10 or 50 mg/kg, im) 30 min before S. ent eritidis LPS (2 mu g/kg, iv) or before PGE(2) microdialyzed into the P OA (1 mu g/mu l at 2 mu l/min for 2.5 h) and during PGE(2) infused int o 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 associate d 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 onse t; thereafter, PGE(2) was significantly reduced by comparison with con trols. Indomethacin at 50 mg/kg completely abolished both the fever an d the increased levels of PGE(2) in the POA; the fever induced by PGE( 2) microdialyzed into the POA was not affected by indomethacin pretrea tment. The intracarotid infusion of PGE(2) produced T-c falls and no i ncrease in preoptic PGE(2) levels. The indomethacin-induced blockade o f fever and inhibition of the associated increase in preoptic PGE(2) l evels 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 po ssibility that PGE(2) formed outside of the brain penetrates the POA a nd induces fever. Thus, in guinea pigs, the PGE(2) associated with LPS -induced fever may be synthesized in the POA.