Abstract
It is generally believed that fever is mediated by certain cytokines produced by immune cells activated by exogenous pyrogens, e.g., lipopolysaccharides (LPS), released into the circulation and transported to the brain. There, the cytokines are thought to stimulate prostaglandin (PG) E 2 production within the organum vasculosum laminae terminalis region. PGE, then may act as a febrigenic mediator locally or in the surrounding preoptic area (POA). However, whereas the increases in preoptic PGE 2 and body (core) temperature (T c) following the intravenous (i.0 administration of LPS correlate temporally, cytokine levels in blood lag both these increases. From recent data in the literature, we have conjectured that a possible, alternative communication pathway between the i.v. LPS-activated immune system and brain PGE 2 may be provided by the vagi. To test this possibility, we measured the levels of PGE 2 in the extracellular fluid of the POA (collected by microdialysis) of conscious, subdiaphragmatically vagotomized or sham-operated guinea pigs following LPS administration (2 μg/kg; i.v.); controls received pyrogen-free saline (PFS). The effluents from the microdialysis probes were collected over 30-min periods throughout the experiments and the samples analyzed by radioimmunoassay; (T c) was monitored continuously using thermocouples inserted 5 cm into the colon. LPS induced a biphasic fall in T c and failed to increase preoptic PGE 2 levels in the vagotomized guinea pigs ( n = 10), whereas in their sham-operated controls ( n = 10) it induced increases in both preoptic PGE 2 and (T c) within 15 min after its injection; PFS ( n = 13) had no effect on either variable. We postulate that peripheral immune cell-derived signals may be transmitted via the vagi to the medulla. From other data, we suggest further that they may be conveyed from here via the ventral noradrenergic bundle to the POA region, where the released norepinephrine induces the local synthesis of PGE 2 and, hence, fever onset.
Published Version
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