Kisspeptin, Neurokinin B, and Dynorphin Act in the Arcuate Nucleus to Control Activity of the GnRH Pulse Generator in Ewes

Abstract

Recent work has led to the hypothesis that kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus play a key role in GnRH pulse generation, with kisspeptin driving GnRH release and neurokinin B (NKB) and dynorphin acting as start and stop signals, respectively. In this study, we tested this hypothesis by determining the actions, if any, of four neurotransmitters found in KNDy neurons (kisspeptin, NKB, dynorphin, and glutamate) on episodic LH secretion using local administration of agonists and antagonists to receptors for these transmitters in ovariectomized ewes. We also obtained evidence that GnRH-containing afferents contact KNDy neurons, so we tested the role of two components of these afferents: GnRH and orphanin-FQ. Microimplants of a Kiss1r antagonist briefly inhibited LH pulses and microinjections of 2 nmol of this antagonist produced a modest transitory decrease in LH pulse frequency. An antagonist to the NKB receptor also decreased LH pulse frequency, whereas NKB and an antagonist to the receptor for dynorphin both increased pulse frequency. In contrast, antagonists to GnRH receptors, orphanin-FQ receptors, and the N-methyl-D-aspartate glutamate receptor had no effect on episodic LH secretion. We thus conclude that the KNDy neuropeptides act in the arcuate nucleus to control episodic GnRH secretion in the ewe, but afferent input from GnRH neurons to this area does not. These data support the proposed roles for NKB and dynorphin within the KNDy neural network and raise the possibility that kisspeptin contributes to the control of GnRH pulse frequency in addition to its established role as an output signal from KNDy neurons that drives GnRH pulses.

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

“…Here we extend these findings by demonstrating in OVX ewe that the diminution of plasma LH levels is specifically due to an interruption of the LH pulse. The prolongation of the LH pulse interval observed here in response to iv treatment with an NK3R antagonist is consistent with previous observations made in ewe after the infusion of NK3R antagonists directly into the brain (17,27). The restoration of the LH pulse in the current study is coincident with the decline of ESN364 plasma levels below approximately 1.5 M, data that are generally consistent with the PK-PD relationships previously established for ESN364 in monkeys (11).…”

Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion

“…Importantly, increases in extracellular kisspeptin levels within the region of the ARN can correlate with pulsatile GnRH secretion (48) and injection of Gpr54 antagonists into the ARN region decreases LH pulse frequency (49,50). The location of Gpr54 antagonism within those studies is unknown and may possibly be at the level of the Gpr54-expressing GnRH neuron dendron/terminals within and adjacent to the ARN, where they would suppress the putative episodic kisspeptin drive to GnRH secretion.…”

The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction

“…In support of this notion, Luque et al (2007) noted a defective expression of Kiss1 in Npyknockout mice and suggested that a normal NPY neuronal network is essential for KP-containing neurons to function accurately. Similarly, dynorpin A and neurokinin B coexpressions have been identified on KPergic neurons (Goodman et al 2013). It will be interesting to know whether KP and GnIH neurons contain receptors for AgRP, NPY, GALP, CART, and POMC or receive afferent projections from these neuronal networks of the feeding and satiety center.…”