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.

Role of central and peripheral opioid receptors in the cardioprotection of intravenous morphine preconditioning

“…Although studies revealed that central nervous system (CNS) participation is probably required for the effect intravenous opioid preconditioning [6] and not for IPC [9], there is no direct evidence to demonstrate central ORs mediates the protective effect of MPC and IPC. In this study, we intrathecally or intravenously administered naloxone methiodide (NM), a quaternary non-selective ORs antagonist, which dose not cross the blood brain barrier [10], to investigate the role of central and peripheral ORs in the cardioprotective effects of MPC and IPC.…”

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats

“…POMC peptide is a precursor for several biologically active neuropeptides including ␣-MSH, ␤-endorphin, and ACTH (40). Of particular interest to the current study is ␤-endorphin as blockade of -opioid receptor, one of the receptors for ␤-endorphin either by specific antagonists or genetic mutation abrogates the fever response induced by classical pyrogens including LPS (4,5,16,44,61) via several different mechanisms, including a central hypothermic action, peripheral vasodilation, and peripheral antipyretic activity (44).…”

CCK2receptor nullification attenuates lipopolysaccharide-induced sickness behavior

“…When administered to guinea pigs intravenously, the opioid antagonist, naloxone, decreased the first and suppressed the second febrile phase elicited by LPS and abolished the febrile changes evoked by interferon-␣2, TNF-␣, and IL-6 (9). Although centrally administered -opioid receptor antagonism attenuated LPS-induced fever in rats (4) but not guinea pigs (62), peripheral administration attenuated fever in both species, suggesting that circulating opioids may play a role in fever production (9,62). Given that the opioid system is upregulated in CCK 2 KO mice (58), one may have hypothesized an increased febrile response to LPS in this strain.…”