We have previously found that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) axis activity following both peripheral and central administration. This effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. We have now demonstrated that this effect is also observed with hybrid rHu-IFN-alpha A/D, rat kidney fibroblast-derived IFN-alpha, and recombinant rat IFN-alpha preparations. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha2A(10(03)U), rHu-IFN-alpha A/D (10(4)U), and of Rat-IFN-alpha (1-10U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all four IFN-alpha preparations. No increases in plasma corticosterone concentrations were observed with doses of rHu-IFN-alpha A/D up to 10(6)U (i.p.) or 7x10(5)U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5x10(3)U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5x10(3)U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A(10(4)U, i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus (PVN) neurons tested, including putative corticotropin-releasing factor-(CRF)-secreting neurons antidromically identified as projecting to the median eminence. Similarly, iontophoretic application of rHu-IFN-alpha 2A decreased the electrical activity of such cells. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated, at least in part, by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons.