{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:54Z","timestamp":1753892094654,"version":"3.41.2"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Serotonin (5-HT) is known to act <jats:italic>via<\/jats:italic> multiple 5-HT receptors at spinal and supraspinal levels to regulate micturition. However, the contribution of peripheral 5-HT and its receptors in bladder physiology and pathology is not very well understood, despite evidence showing expression of multiple 5-HT receptors in the bladder wall and 5-HT may activate bladder afferent nerves. The current study was designed to investigate the possible role of 5-HT<jats:sub>4<\/jats:sub>R in modulation of the sensitivity of bladder afferents to bladder filling. Immunofluorescent staining showed abundant 5-HT<jats:sub>4<\/jats:sub>R immunoreactivity largely confined to the uroepithelium in wild type (WT) but not 5-HT<jats:sub>4<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> mice. In the <jats:italic>ex vivo<\/jats:italic> bladder-pelvic nerve preparation, intravesical application of the 5-HT<jats:sub>4<\/jats:sub>R agonist RS67333 (1\u201330\u00a0\u03bcm) caused concentration-dependent decreases of the pelvic nerve response to bladder filling. Such effect was not observed in the presence of 5-HT<jats:sub>4<\/jats:sub>R antagonist GR125487 or in 5-HT<jats:sub>4<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> preparations. A cohort of 5-HT<jats:sub>4<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> and WT control mice were treated with intraperitoneal injections of cyclophosphamide (CYP) (75\u00a0mg\/kg, three times at 2\u00a0days interval) to induce chronic cystitis. Void spot analysis showed that CYP-treated 5-HT<jats:sub>4<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> mice urinated more frequently than their CYP-treated WT counterparts. Concomitantly, bladder afferents of CYP-treated 5-HT<jats:sub>4<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed exaggerated sensitivity to bladder filling in comparison with the CYP-treated WT controls. These data suggest that 5-HT<jats:sub>4<\/jats:sub>R expressed on uroepithelial cells plays an inhibitory role in mechanosensory transduction in the bladder. Loss of 5-HT<jats:sub>4<\/jats:sub>R-mediated inhibition may enhance bladder afferent sensitivity and exacerbate bladder overactivity in pathological conditions. We propose that 5-HT<jats:sub>4<\/jats:sub>R agonists might be exploited for the treatment of overactive and painful bladder symptoms.<\/jats:p>","DOI":"10.3389\/fphys.2022.990178","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T07:00:35Z","timestamp":1663052435000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Activation of uroepithelial 5-HT4R inhibits mechanosensory activity of murine bladder afferent nerves"],"prefix":"10.3389","volume":"13","author":[{"given":"Yu","family":"Lu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weifang","family":"Rong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1590\/1806-9282.20201166","article-title":"The effect of Mirabegron and Duloxetine combination in mixed-type urinary incontinence treatment","volume":"67","author":"Ariman","year":"2021","journal-title":"Rev. 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