title: The inhibitory effects of neurokinin B on GnRH pulse generator frequency in the female rat.
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 17β-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 17β-estradiol-replaced OVX animals. Pretreatment with a selective Dyn receptor (κ 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/κ opioid receptor-dependent fashion.
authors: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors: James S
authors: JS
authors: Kinsey-Jones
authors: Pasha
authors: P
authors: Grachev
authors: Xiao Feng
authors: XF
authors: Li
authors: Yuan Shao
authors: YS
authors: Lin
authors: Stuart R
authors: SR
authors: Milligan
authors: Stafford L
authors: SL
authors: Lightman
authors: Kevin T
authors: KT
authors: O'Byrne
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004399:Dynorphins / Q000502:physiology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D059648:Kisspeptins / Q000494:pharmacology / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism; D009292:Narcotic Antagonists; D015287:Neurokinin B / Q000494:pharmacology* / Q000502:physiology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology; D000074502:Receptors, Kisspeptin-1; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000502:physiology; D011957:Receptors, Opioid / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C491406:Kiss1 protein, rat; C492247:Kiss1r protein, rat; D059648:Kisspeptins; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018042:Receptors, Neurokinin-3; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C030738:dynorphin receptor; C054724:senktide; D013373:Substance P; D007987:Gonadotropin-Releasing Hormone; D004399:Dynorphins; D015287:Neurokinin B; D007986:Luteinizing Hormone