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Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon\u2010projecting sensory neurons suggests that non\u2010neuronal cells may contribute to TRPV4\u2010mediated nociceptor stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging when cultured alone or co\u2010cultured with colonic mucosa.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co\u2010cultured with colonic mucosal cells produced a marked increase in intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      to GSK1016790A compared with neurons cultured alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.17408","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T19:44:15Z","timestamp":1733255055000},"page":"1324-1340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2703-6957","authenticated-orcid":false,"given":"Michelle Y.","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke W.","family":"Paine","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sagnat","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Bello","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"},{"name":"Department of Pharmacy, School of Medicine and Surgery University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Oldroyd","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-6276","authenticated-orcid":false,"given":"Farideh","family":"Javid","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Applied Sciences University of Huddersfield  Huddersfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-637X","authenticated-orcid":false,"given":"Matthew T.","family":"Harper","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R. 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