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

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Authors

Grachev, Pasha
Li, X.F.
Hu, M.H.
Li, S.Y.
Millar, Robert P.
Lightman, Stafford L.
O'Byrne, Kevin T.

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The Endocrine Society

Abstract

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/dynorphinAneurons. Agonists of the neurokininB(NKB) receptor (NK3R) have beenshown 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 stressinduced suppression of the GnRH pulse generator. To investigate this ovariectomized rats, iv administered with Escherichia coli lipopolysaccharide (LPS) following intracerebroventricular pretreatment with NK3R or -opioid receptor (Dyn receptor) antagonists, were subjected to frequent blood sampling for hormone analysis. Antagonism of NK3R, but not -opioid receptor, blocked the suppressive effect of LPS challengeonLHpulse 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.

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Keywords

Stress, Reproduction, Acute systemic stress, GnRH pulse generator, Neurokinin B (NKB), NKB/NK3R signaling

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Citation

Grachev, P, Li, XF, Hu, MH, Li, SY, Millar, RP, Lightman, SL & O'Byrne, KT 2014, 'Neurokinin B signaling in the female rat : a novel link between stress and reproduction', Endocrinology, vol. 155, no. 7, pp. 2589-2601.