Naloxone differentially alters fevers induced by cytokines

Interferon-alpha (IFN-alpha), a cytokine acting as an endogenous pyrogen and a putative activator of the opioid system, binds to opiate receptors in vitro. The mu opioid receptor antagonist, naloxone hydrochloride (NLX), attenuates IFN-alpha-induced increases in the firing rate of cold-sensitive neurons within thermosensitive areas of the brain. The influence of NLX on fevers induced by central endogenous pyrogens was investigated in rats. Subcutaneous (SQ) injection of NLX (1 mg/kg) was made 30 min prior to intracerebroventricular (ICV) injection of IFN-alpha 2b (7900IU). Alternatively, NLX (10 or 80 micrograms) was microinjected ICV 30 min prior to administration of IFN-alpha 2b. Administered SQ, NLX attenuated the febrile response to IFN-alpha 2b. In contrast, central (ICV) NLX did not attenuate fevers induced by IFN-alpha 2b. Animals previously exposed to both IFN-alpha 2b and NLX (SQ or ICV) subsequently lost their sensitivity to this cytokine, and also showed diminished reactivity to human recombinant interleukin-1 beta (hrIL-1 beta; 10 ng) and prostaglandin E2 (PGE2; 250 ng). These results suggest that systemic and central elements of the opioid system may play differential roles in temperature regulation. Previous administration of NLX and IFN-alpha 2b may alter the sensitivity of the CNS to subsequent injections of different pyrogens.