We have previously shown that the febrile response of guinea pigs to lipopolysaccharide (LPS) is attenuated by the subcutaneous administration of the tertiary mu-receptor opioid antagonist naloxone-hydrochloride (Nal-HCl). Because Nal-HCl readily crosses the blood-brain barrier (BBB), this study was undertaken to investigate whether its effect on fever is mediated peripherally or centrally. For this, the effects of 1) Nal-HCl (23 and 46 mumol/kg sc), 2) the quaternary opioid antagonists Nal-methiodide (Nal-mI, 46 and 92 mumol/kg sc) and Nal-methobromide (Nal-mBr, 92 mumol/kg sc), which do not cross the BBB, and 3) intracerebroventricular Nal-HCl (0.25 and 1.25 mumol) on the febrile response to intravenous S. enteritidis LPS (2 micrograms/kg) were investigated in conscious guinea pigs. Under afebrile conditions, both Nal-HCl (whether administered sc or icv) and its quaternary analogues induced hypothermic responses. Peripheral Nal-HCl, Nal-mI, and Nal-mBr also attenuated both phases of the characteristically biphasic LPS fever. The thermal effects of the peripheral opioid antagonists, both tertiary and quaternary, were associated with cutaneous vasodilation. Intracerebroventricularly administered Nal-HCl did not evoke any attenuation of fever. The analysis of the data shows that Nal-HCl possesses three different thermoregulatory actions: a central hypothermic action, a peripheral thermolytic action (which is due to, at least partly, cutaneous vasodilation), and a peripheral antipyretic action. The latter effect suggests that, in guinea pigs, circulating opioids may have a role in fever production.
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.
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