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The pulsatile release of gonadotropin-releasing hormone (GnRH) is a key feature of the hypothalamic-pituitary-gonadal axis. Kisspeptin neurons in the arcuate nucleus (ARC) trigger GnRH neuronal activity, but how GnRH neurons return to baseline electrical activity is unknown. Nociceptin/orphanin-FQ (OFQ) is an inhibitory neuromodulator. ARC proopiomelanocortin (POMC) neurons, known to receive inputs from ARC kisspeptin neurons, contact GnRH neurons and coexpress OFQ in the rat. In the present study, the effect of OFQ(1-13) on GnRH neurons was determined in the mouse. We identified transcripts for the OFQ receptor [opioid receptor like 1 (ORL1)] in GnRH neurons, and, using two-model systems (explants and slices), we found that OFQ exerted a potent inhibition on GnRH neurons, with or without excitatory inputs. We confirmed that the inhibition was mediated by ORL1 via G i/o -protein coupling. The inhibition, occurring independently of levels of intracellular cyclic adenosine monophosphate, was sensitive to inwardly rectifying potassium channels. The only specific blocker of G i/o -protein-coupled inwardly rectifying potassium (GIRK) channels, tertiapin-Q (TPNQ), was ineffective in the inhibition of OFQ. Two GIRK activators, one sharing the binding site of TPNQ and one active only on GIRK1-containing GIRK channels, failed to trigger an inhibition. In contrast, protein kinase C phosphorylation activation, known to inhibit GIRK2-mediated currents, prevented the OFQ inhibition. These results indicate a specific combination of GIRK subunits, GIRK2/3 in GnRH neurons. In vivo , double-labeled OFQ/POMC fibers were found in the vicinity of GnRH neurons, and OFQ fibers apposed GnRH neurons. Together, this study brings to light a potent neuromodulator of GnRH neurons.

Nociceptin/Orphanin-FQ Inhibits Gonadotropin-Releasing Hormone Neurons via G-Protein-Gated Inwardly Rectifying Potassium Channels