Role of intrapreoptic norepinephrine in endotoxin-induced fever in guinea pigs.

The peripheral administration of pyrogens has been shown previously to affect the activity of central noradrenergic neurons, but the effects have been variable and no consensus has emerged regarding their functional significance. Because norepinephrine (NE) microdialyzed into the preoptic area (PO) of the anterior hypothalamus of conscious guinea pigs is hypothermizing, the possibility was investigated whether NE might be a febrilytic rather than a febrigenic mediator. Intravenous injections of Salmonella enteritidis lipopolysaccharide (2.0 micrograms/kg) evoked a bimodal fever, which was attenuated in a dose-dependent manner by NE microdialyzed (10 or 20 micrograms/microliters at a rate of 2 microliters/min for various durations) into the PO. The alpha 2-adrenergic receptor antagonists rauwolscine (1 or 2 micrograms/microliters) and yohimbine (1 microgram/microliter) microdialyzed intrapreoptically significantly reduced the trough of body (core) temperature (Tc) between the first and second peaks of the bimodal fever and prolonged the overall febrile course. None of these effects was associated with changes in skin temperature. The level of NE (assayed by high-performance liquid chromatography with electrochemical detection) in the preoptic extracellular fluid collected by intracerebral microdialysis was significantly elevated at the end of each rising phase of the bimodal fever, just before or about the time when Tc began to fall, compared with pyrogen-free saline controls at the same times. These results suggest that intrapreoptic NE may have a thermolytic effect on fever by reducing metabolic heat production and may thus play a physiological role in the initiation of febrilysis in guinea pigs.