Peripheral naloxone attenuates lipopolysaccharide fever in guinea pigs by an action outside the blood-brain barrier

Abstract

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.