Nociceptin-Opioid-Related Nociceptin Receptor 1 Signaling Partly Mediates Glucoprivic Suppression of Luteinizing Hormone Pulses in Female Rats: Arcuate Kiss1 Neurons as a Possible Target for Nociceptin.

Abstract

Introduction: During malnutrition, mammalian reproductive functions are suppressed by inhibition of the pulsatile release of gonadotropin-releasing hormone (GnRH)/gonadotropins. This study aimed to investigate whether nociceptin-opioid-related nociceptin receptor 1 (OPRL1) signaling mediates glucoprivic suppression of luteinizing hormone (LH) pulses in female rats.

Methods and results: RNA sequencing analysis of tdTomato-positive arcuate (ARC) kisspeptin neurons obtained from Kiss1 (kisspeptin gene)-Cre/Cre-dependent tdTomato reporter female rats showed that Oprl1 messenger RNA expression was evident in ARC kisspeptin neurons. Double in situ hybridization for Kiss1 and Oprl1 or prepronociceptin gene (Pnoc) revealed that approximately 20% of Kiss1-expressing cells co-expressed Oprl1, but not Pnoc in ovariectomized (OVX) wild-type rats treated with diestrus levels of estradiol-17β (low E2). Administration of [N-Phe1]-orphanin FQ (1-13) amide (NC13), a selective OPRL1 antagonist, to the third ventricle (3V) transiently reversed the suppression of LH pulses induced by intravenous (iv) 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, in OVX + low E2 rats. The frequency of LH pulses during the first hour of the 3-h sampling period was significantly higher in 3V NC13-treated rats than in vehicle-treated controls. In contrast, 3V NC13 administration failed to affect LH pulses in OVX + low E2 rats without iv 2DG treatment. Furthermore, iv 2DG treatment significantly increased the percentage of fos-positive ARC Pnoc-expressing cells in OVX + low E2 rats.

Conclusion: These results indicate that ARC nociceptin-OPRL1 signaling partly mediates the glucoprivic suppression of LH pulses and that nociceptin may directly suppress ARC kisspeptin neurons, the GnRH/LH pulse generator in female rats.