| Autor: |
Saphier, D., Roerig, S.C., Ito, C., Vlasak, W.R., Farrar, G.E., Broyles, J.E., Welch, J.E. |
| Zdroj: |
Brain, Behavior, and Immunity; March 1994, Vol. 8 Issue: 1 p37-56, 20p |
| Abstrakt: |
In our earlier studies we have demonstrated that recombinant human interferon-α2A (rHu-IFN-α2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by μ-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-αA/D, and a leucocyte-derived rat IFN-α preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-α2A (103U), rHu-IFN-αA/D (104U), and of Rat-IFN-α (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-α preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-α2A up to 106U (i.p.) or 7 × 105U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-α (103and 5 × 103U). The inhibitory effects of all of the IFN-α preparations tested were antagonized by naloxone, but the stimulatory effects of 5 × 103U Rat-IFN-α were not. Injections of rHu-IFN-α2A (104U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-α are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-α to μ-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly μ-receptors, are sensitive to rHu-IFN-α2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.7-11.04) nMfor this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma × rat glioma hybrid cells (expressing δ-receptors) were affected by rHu-IFN-α2A. In addition, preliminary data indicated that the opioid receptor antagonist, naltrexone (0.1 μM), was able to prevent the inhibitory effect of rHu-IFN-α2A on adenylyl cyclase activity. Thus, the implication is that (μ-)opioid receptors are involved in the transduction of some central nervous system effects of IFN-α. |
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