Possible sequence of pyrogenic afferent processing in the POA

(1) It is generally considered that fever is modulated in the preoptic-anterior hypothalamic area (POA) in response to signaling by pyrogenic cytokines elaborated in the periphery by mononuclear phagocytes and the consequent induction of prostaglandin (PG)E2 in the POA. The mechanism of the centripetal transmission of this pyrogenic signal, however, is controversial. One hypothesis suggests that it is conveyed via the vagus to the nucleus tractus solitarius and from there to the POA via the ventral noradrenergic bundle, causing the intraPOA release of norepinephrine (NE) which then stimulates the production of PGE2. (2) In this article, we review recent data from our laboratory showing that NE microdialyzed into the POA of conscious guinea pigs or injected intracerebroventricularly into conscious mice indeed evokes two distinct core temperature (Tc) rises, viz., one (AR)-mediated, rapid in onset and PGE2-independent, and the other , delayed and COX-2/PGE2-dependent. (3) We further present new data suggesting that the febrile response of conscious guinea pigs to intraperitoneally injected lipopolysaccharide (LPS) is mediated by intraPOA NE in accord with the above sequence, i.e., via to initiate the first, PGE2-independent elevation of Tc, and via to induce the delayed production of COX-2-dependent PGE2 and the continued rise of Tc. (4) These results thus validate the presumptive involvement of NE in LPS fever induction in guinea pigs. [Copyright &y& Elsevier]