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 (ARC) kisspeptin/neurokinin B/dynorphin A (KNDy) 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 (OVX) rats, intravenously (iv) administered with Escherichia coli lipopolysaccharide (LPS) following intracerebroventricular (icv) pretreatment with NK3R or kappa-opioid receptor (KOR; Dyn receptor) antagonists, were subjected to frequent blood sampling for hormone analysis. Antagonism of NK3R, but not KOR, blocked the suppressive effect of LPS challenge on LH pulse frequency. Neither antagonist affected LPS-induced corticosterone (CORT) secretion. ARC NKB neurons project to the paraventricular nucleus (PVN) - the major hypothalamic source of the stress-related neuropeptides corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), which have been implicated in the stress-induced suppression of the HPG axis. A separate group of OVX rats was, therefore, used to address the potential involvement of central CRH and/or AVP signaling in the suppression of LH pulsatility induced by icv 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 CORT 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