Suppression of the GnRH Pulse Generator by Neurokinin B Involves a -Opioid Receptor-Dependent Mechanism

Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and -opioid receptor (KOR), respec-tively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebro-ventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons.Weperformeda series of in vivoneuropharmacological experiments aiming todetermine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the inter-action between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First,we investigated theeffectof intra-ARCadministrationof the selectiveNK3Ragonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion i