MODE OF ACTION OF INTERLEUKIN-1 IN SUPPRESSION OF PITUITARY LH-RELEASE IN CASTRATED MALE-RATS

These studies were undertaken to elucidate the mechanisms whereby the cytokine, Interleukin (IL-1) suppresses pituitary LH release in orchidectomized rats. Since LH secretion is pulsatile in castrated rats, the effects of IL-1 on the components of the LH pulsatility were assessed. Intracerebroventricular (i.c.v.) administration of IL-1alpha or IL-1beta suppressed LH release, but IL-1beta was relatively more effective than IL-1alpha in terms of the onset (IL-1beta = 30 min; IL-1alpha = 105 min) as well as the magnitude and duration of LH suppression. Further, the marked suppression of LH secretion in IL-1beta-treated rats was found to be due to significant reductions both in the frequency and amplitude of LH episodes. We next evaluated whether the IL-1beta-induced suppression of LH release was mediated by either of the two inhibitory hypothalamic peptidergic systems, corticotrophin releasing hormone (CRH) and endogenous opioid peptides (EOP). Passive immunoneutralization of CRH by i.c.v. administration of a specific CRH-antibody, either once at 15 min or twice at 75 and 15 min before IL-1beta injection, failed to block the suppressive effects of IL-1beta on LH release. Similarly, pharmacological blockade of CRH by i.c.v. injection of the CRH receptor antagonist, alpha-helical CRH9-41 15 min before IL-1beta was ineffective. However, i.v. infusion of the opiate receptor antagonist, naloxone, which on its own had no effect on LH secretion, counteracted the inhibitory effects of IL-1beta. To further identify the opiate receptor subtype involved, we utilized specific opiate receptor subtype antagonists. We observed that neither blockade of delta receptors with naltrindole, nor blockade of kappa receptors with nor-binaltorphimine dihydrochloride, altered the course of LH suppression seen after IL-1beta injection. However, prior blockade of mu1 opiate receptors with beta-funaltrexamine hydrochloride, completely reversed the inhibitory effects of IL-1beta on LH release. These results show that IL-1beta suppresses both the frequency and amplitude of LH discharge in two-week castrated rats. Further pharmacologic evidence shows that IL-1beta-induced suppression of LH secretion may involve stimulation of hypothalamic endogenous opioids which presumably act via the hypothalamic mu1 opiate receptor subtype, and that stimulation of hypothalamic CRH release may not be essential in manifestation of the inhibitory effects of IL-1beta on LH release.