Neurokinin B Signaling in the Female Rat: a Novel Link Between Stress and Reproduction

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 hypo-estrogenic 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 kappa-opioid receptor (Dyn receptor) antagonists, were subjected to frequent blood sampling for hormone analysis. Antagonism of NK3R, but not kappa-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.