E. Sehic et al., HYPOTHALAMIC PROSTAGLANDIN E(2) DURING LIPOPOLYSACCHARIDE-INDUCED FEVER IN GUINEA-PIGS, Brain research bulletin, 39(6), 1996, pp. 391-399
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.