Estrogen-Dependent Regulation of Neurokinin 3 Receptor-Mediated Uterine Contractility in the Rat

• Published in: Biology of reproduction 2002-11, Vol.67 (5), p.1480-1487
• Main Authors: CRANE, Linda H, WILLIAMS, Melanie J, NIMMO, Alan J, HAMLIN, Gary P
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Animals; Biological and medical sciences; Capsaicin - pharmacology; Dose-Response Relationship, Drug; Estrogens - pharmacology; Estrogens - physiology; Estrus - physiology; Female; Fundamental and applied biological sciences. Psychology; Hormone metabolism and regulation; In Vitro Techniques; Mammalian female genital system; Ovariectomy; Peptide Fragments - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1 - drug effects; Receptors, Neurokinin-1 - metabolism; Receptors, Neurokinin-2 - drug effects; Receptors, Neurokinin-2 - metabolism; Receptors, Neurokinin-3 - agonists; Receptors, Neurokinin-3 - metabolism; Substance P - analogs & derivatives; Substance P - pharmacology; Uterine Contraction - drug effects; Uterine Contraction - physiology; Uterus - drug effects; Uterus - physiology; Vertebrates: reproduction
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.101.002022

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.