NALOXONE DIFFERENTIALLY ALTERS FEVERS INDUCED BY CYTOKINES

Interferon-alpha (IFN-alpha), a cytokine acting as an endogenous pyrog en and a putative activator of the opioid system, binds to opiate rece ptors in vitro. The mu opioid receptor antagonist, naloxone hydrochlor ide (NLX), attenuates IFN-alpha-induced increases in the firing rate o f cold-sensitive neurons within thermosensitive areas of the brain. Th e influence of NLX on fevers induced by central endogenous pyrogens wa s investigated in rats. Subcutaneous (SQ) injection of NLX (1 mg/kg) w as made 30 min prior to intracerebroventricular (ICV) injection of IFN -alpha 2(b) (7900 IU). Alternatively, NLX (10 or 80 mu g) was microinj ected ICV 30 min prior to administration of IFN-alpha 2(b). Administer ed SQ, NLX attenuated the febrile response to IFN-alpha 2(b). In contr ast, central (ICV) NLX did not attenuate fevers induced by IFN-alpha 2 (b). Animals previously exposed to both IFN-alpha 2(b) and NLX (SQ or ICV) subsequently lost their sensitivity to this cytokine, and also sh owed diminished reactivity to human recombinant interleukin-1 beta (hr IL-1 beta; 10 ng) and prostaglandin E(2) (PGE(2); 250 ng). These resul ts suggest that systemic and central elements of the opioid system may play differential roles in temperature regulation. Previous administr ation of NLX and IFN-alpha 2(b) may alter the sensitivity of the CNS t o subsequent injections of different pyrogens. (C) 1997 Elsevier Scien ce Ltd.