Neurokinin B signaling in the female rat: a novel link between stress and reproduction

P Grachev, X F Li, M H Hu, S Y Li, R P Millar, S L Lightman, K T O'Byrne

Research output: Contribution to journalArticle (Academic Journal)peer-review


Acute systemic stress disrupts reproductive function by inhibiting pulsatile gonadotropin secretion. The underlying mechanism involves stress-induced suppression of the GnRH pulse generator, the functional unit of which is considered to be the hypothalamic arcuate nucleus kisspeptin/neurokinin B/dynorphin A neurons. Agonists of the neurokinin B (NKB) receptor (NK3R) have been shown to suppress the GnRH pulse generator, in a dynorphin A (Dyn)-dependent fashion, under hypoestrogenic conditions, and Dyn has been well documented to mediate several stress-related central regulatory functions. We hypothesized that the NKB/Dyn signaling cascade is required for stress-induced suppression of the GnRH pulse generator. To investigate this ovariectomized rats, iv administered with Escherichia coli lipopolysaccharide (LPS) following intracerebroventricular pretreatment with NK3R or κ-opioid receptor (Dyn receptor) antagonists, were subjected to frequent blood sampling for hormone analysis. Antagonism of NK3R, but not κ-opioid receptor, blocked the suppressive effect of LPS challenge on LH pulse frequency. Neither antagonist affected LPS-induced corticosterone secretion. Hypothalamic arcuate nucleus NKB neurons project to the paraventricular nucleus, the major hypothalamic source of the stress-related neuropeptides CRH and arginine vasopressin (AVP), which have been implicated in the stress-induced suppression of the hypothalamic-pituitary-gonadal axis. A separate group of ovariectomized rats was, therefore, used to address the potential involvement of central CRH and/or AVP signaling in the suppression of LH pulsatility induced by intracerebroventricular administration of a selective NK3R agonist, senktide. Neither AVP nor CRH receptor antagonists affected the senktide-induced suppression of the LH pulse; however, antagonism of type 2 CRH receptors attenuated the accompanying elevation of corticosterone levels. These data indicate that the suppression of the GnRH pulse generator by acute systemic stress requires hypothalamic NKB/NK3R signaling and that any involvement of CRH therewith is functionally upstream of NKB.

Original languageEnglish
Pages (from-to)2589-601
Number of pages13
Issue number7
Publication statusPublished - Jul 2014


  • Animals
  • Antidiuretic Hormone Receptor Antagonists
  • Arcuate Nucleus of Hypothalamus/cytology
  • Corticosterone/blood
  • Corticotropin-Releasing Hormone/pharmacology
  • Female
  • Gonadotropin-Releasing Hormone/metabolism
  • Injections, Intraventricular
  • Lipopolysaccharides/administration & dosage
  • Luteinizing Hormone/metabolism
  • Neurokinin B/metabolism
  • Neurons/drug effects
  • Ovariectomy
  • Peptide Fragments/administration & dosage
  • Pyrimidines/pharmacology
  • Pyrroles/pharmacology
  • Quinolines/administration & dosage
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors
  • Receptors, Neurokinin-3/agonists
  • Receptors, Vasopressin/metabolism
  • Reproduction/physiology
  • Signal Transduction/drug effects
  • Stress, Physiological/physiology
  • Substance P/administration & dosage

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