The Inhibitory Effects of Neurokinin B on GnRH Pulse Generator Frequency in the Female Rat

James S. Kinsey-Jones, Pasha Grachev, Xiao Feng Li, Yuan Shao Lin, Stuart R. Milligan, Stafford L. Lightman, Kevin O'Byrne

Research output: Contribution to journalArticlepeer-review

103 Citations (Scopus)

Abstract

Neurokinin B (NKB) and its receptor (neurokinin-3 receptor) are coexpressed with kisspeptin and dynorphin A (Dyn) within neurons of the hypothalamic arcuate nucleus, the suggested site of the GnRH pulse generator. It is thought that these neuropeptides interact to regulate gonadotropin secretion. Using the ovariectomized (OVX) and OVX 17 beta-estradiol-replaced rat models, we have carried out a series of in vivo neuropharmacological and electrophysiological experiments to elucidate the hierarchy between the kisspeptin, NKB, and Dyn signaling systems. Rats were implanted with intracerebroventricular cannulae and cardiac catheters for frequent (every 5 min) automated serial blood sampling. Freely moving rats were bled for 6 h, with intracerebroventricular injections taking place after a 2-h control bleeding period. A further group of OVX rats was implanted with intra-arcuate electrodes for the recording of multiunit activity volleys, which coincide invariably with LH pulses. Intracerebroventricular administration of the selective neurokinin-3 receptor agonist, senktide (100-600 pmol), caused a dose-dependent suppression of LH pulses and multiunit activity volleys. The effects of senktide did not differ between OVX and 17 beta-estradiol-replaced OVX animals. Pretreatment with a selective Dyn receptor (kappa opioid receptor) antagonist, norbinaltorphimine (6.8 nmol), blocked the senktide-induced inhibition of pulsatile LH secretion. Intracerebroventricular injection of senktide did not affect the rise in LH concentrations after administration of kisspeptin (1 nmol), and neither did kisspeptin preclude the senktide-induced suppression of LH pulses. These data show that NKB suppresses the frequency of the GnRH pulse generator in a Dyn/kappa opioid receptor-dependent fashion. (Endocrinology 153: 307-315, 2012)
Original languageEnglish
Pages (from-to)307-315
Number of pages9
JournalEndocrinology
Volume153
Issue number1
DOIs
Publication statusPublished - Jan 2012

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