Endogenous Opioid Peptides Mediate the Interleukin-1 Induced Inhibition of the Release of Luteinizing Hormone (LH)-Releasing Hormone and LH*

Abstract

We have reported recently that central administration of both the alpha- and beta-subtypes of the cytokine interleukin-1 (IL-1) inhibited the estrogen-progesterone-induced LH surge in ovariectomized (ovx) rats. This inhibition was probably due to a central effect, since IL-1 alpha and IL-1 beta also suppressed the in vitro LHRH output from the hypothalami of steroid-primed ovx rats. Whether IL-1 inhibits LHRH release by a direct action or via some other neuronal system is not known. Since IL-1 reportedly stimulates the release of POMC peptides, which are known to be inhibitory to the LHRH-LH axis, we have tested the hypothesis that the inhibitory influence of IL-1 may be mediated via activation of hypothalamic opioid peptides. Ovx rats, preimplanted with cannulae in the third ventricle of the brain, were injected with 30 micrograms estradiol benzoate, followed by 2 mg progesterone 48 h later. Three hours after P injection, IL-1 alpha, IL-1 beta, or saline (SAL) was injected intracerebroventricularly (30 ng/3 microliters) at 1300 h, followed immediately by iv infusion of SAL or the opiate antagonist naloxone hydrochloride (NAL; 2 mg/0.6 ml.h) for 2 h. Plasma LH levels were measured in blood samples withdrawn hourly until 1800 h. Both IL-1 alpha and IL-1 beta blocked the afternoon LH surge. NAL infusion into control SAL-injected rats did not alter the LH surge; however, it reversed the IL-1 alpha- and IL-1 beta-induced suppression of the LH surge. To determine whether this reversal of IL-1 suppression of the LH surge was due to NAL action at the hypothalamic level, the preoptic area-medial basal hypothalamus of similarly primed ovx rats was obtained at 1300 h and incubated in vitro in the presence of 10 nM IL-1 alpha or IL-1 beta with or without 100 micrograms/ml NAL. Both subtypes of IL-1 suppressed LHRH output significantly. NAL alone did not affect LHRH release, but it completely reversed the inhibitory effects of the cytokine on LHRH release. These results suggest that IL-1 alpha and IL-1 beta inhibit LHRH-LH release by stimulating the activity of hypothalamic endogenous opioid peptide systems.