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 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.
Division of Women's Health (P.G., X.F.L., M.H.H., S.Y.L., K.T.O.), School of Medicine, King's College London, United Kingdom; Mammal Research Institute (R.P.M.), University of Pretoria, Pretoria, South Africa; Medical Research Council Receptor Biology Unit, University of Cape Town, Cape Town, South Africa; Centre for Integrative Physiology, University of Edinburgh, Scotland; and Henry Wellcome Laboratory for Integrative Neuroscience & Endocrinology (S.L.L.), University of Bristol, Bristol, United Kingdom.
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Grachev
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Millar
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Lightman
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O'Byrne
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism; D015287:Neurokinin B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism; D012098:Reproduction / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D065092:Antidiuretic Hormone Receptor Antagonists; C101628:CP 154526; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011743:Pyrimidines; D011758:Pyrroles; D011804:Quinolines; D018019:Receptors, Corticotropin-Releasing Hormone; D018042:Receptors, Neurokinin-3; D017483:Receptors, Vasopressin; C109112:SB 222200; C054724:senktide; C104416:astressin; D013373:Substance P; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B; D007986:Luteinizing Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone