PERIPHERAL NALOXONE ATTENUATES LIPOPOLYSACCHARIDE FEVER IN GUINEA-PIGS BY AN ACTION OUTSIDE THE BLOOD-BRAIN-BARRIER

We have previously shown that the febrile response of guinea pigs to l ipopolysaccharide (LPS) is attenuated by the subcutaneous administrati on of the tertiary mu-receptor opioid antagonist naloxone-hydrochlorid e (Nal-HCl). Because Nal-HCl readily crosses the blood-brain barrier ( BBB), this study was undertaken to investigate whether its effect on f ever is mediated peripherally or centrally. For this, the effects of 1 ) Nal-HCl (23 and 46 mu mol/kg sc), 2) the quaternary opioid antagonis ts Nal-methiodide (Nal-mI, 46 and 92 mu mol/kg sc) and Nal-methobromid e (Nal-mBr, 92 mu mol/kg sc), which do not cross the BBB, and 3) intra cerebroventricular Nal-HCl (0.25 and 1.25 mu mol) on the febrile respo nse to intravenous S. enteritidis LPS (2 mu g/kg) were investigated in conscious guinea pigs. Under afebrile conditions, both Nal-HCl (wheth er administered sc or icv) and its quaternary analogues induced hypoth ermic responses. Peripheral Nal-HCl, Nal-mI, and Nal-mBr also attenuat ed both phases of the characteristically biphasic LPS fever. The therm al effects of the peripheral opioid antagonists, both tertiary and qua ternary, were associated with cutaneous vasodilation. Intracerebrovent ricularly 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 vasodi lation), and a peripheral antipyretic action. The latter effect sugges ts that, in guinea pigs, circulating opioids may have a role in fever production.