title: Estrogen-dependent regulation of neurokinin 3 receptor-mediated uterine contractility in the rat.
abstract: The receptors for neurokinin 1 (NK1-R), neurokinin 2 (NK2-R), and neurokinin 3 (NK3-R) are expressed and functionally active in the uterus, promoting strong contractions of the myometrium. Previously, we demonstrated that myometrial contractility activated by the NK-Rs is regulated by estrogen. In the current study, we furthered our investigations of the role of estrogen in the regulation of NK3-R-mediated myometrial contractility. Estrogen promotes both heterologous and homologous desensitization of NK3-R-mediated uterine contractility. In tissue obtained from estrogen-dominated rats (ovariectomized estrogen-treated rats and rats in estrus), the magnitude of uterine contractions decreased in response to consecutive additions of the NK3-R-selective agonist senktide. By addition of the fourth dose of agonist, the contractile response was routinely barely above baseline. In contrast, in tissue obtained from non-estrogen-dominated rats consecutive doses of senktide resulted in contractions of identical magnitude. The homologous desensitization was specific to the NK3-R, and the desensitization of the NK3-R-mediated response did not affect the magnitude or nature of uterine contractions in response to NK1-R or NK2-R activation. Furthermore, heterologous and homologous desensitization of NK3-R-mediated contractility is dependent upon the duration of exposure to estrogen. This complex mechanism appears to be important in intact tissue; capsaicin-mediated release of endogenous neuropeptides resulted in a desensitization of response to subsequent stimulation with senktide in estrogen-dominated uterine tissue.
authors.affiliation: Department of Physiology and Pharmacology, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Crane
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Williams
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Nimmo
authors.forename: Gary P
authors.initials: GP
authors.lastname: Hamlin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D004971:Estrus / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D004967:Estrogens; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C054724:senktide; D013373:Substance P; D000109:Acetylcholine; D002211:Capsaicin