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

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Abstract
We have reported recently that central administration of both the α and β-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-lα and IL-1β also suppressed the in vitro LHRH output from the hypothalami of steroidprimed 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 μg estradiol benzoate, followed by 2 mg progesterone 48 h later. Three hours after P injection, IL-lα, IL-1β, or saline (SAL) was injected intracerebroventricularly (30 ngβ (A) 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opiate antagonist naloxone hydrochloride (NAL; 2 mg/0.6 ml-h) for 2 h. Plasma LH levels were measured in blood samples withdrawn hourly until 1800 h. Both IL-la and IL-1β blocked the afternoon LH surge. NAL infusion into control SAL-injected rats did not alter the LH surge; however, it reversed the IL-la- and IL-lβ-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-lα or IL-1β with or without 100 tig/ 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-lα and IL-1β inhibit LHRH-LH release by stimulating the activity of hypothalamic endogenous opioid peptide systems. (Endocrinology127: 2381–2386, 1990)