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Cimetidine, a classical H\n                      <jats:sub>2<\/jats:sub>\n                      blocker, has been shown to inhibit Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchangers (NHEs), thereby potentially suppressing proinflammatory cytokine release.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study examined whether cimetidine alleviates visceral hypersensitivity and colonic hyperpermeability in rat models of IBS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Visceral pain threshold in response to colonic balloon distention was assessed by electromyographic detection of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured using Evans blue uptake in LPS\u2010 and CRF\u2010induced IBS models in male Sprague\u2013Dawley rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Intragastric cimetidine (20\u2013100\u2009mg\/kg daily for 3\u2009days) prevented LPS\u2010induced visceral hypersensitivity and colonic hyperpermeability dose\u2010dependently and also attenuated CRF\u2010induced changes. In contrast, famotidine, another H\n                      <jats:sub>2<\/jats:sub>\n                      blocker, did not replicate these effects. Amiloride, an NHE inhibitor, mimicked cimetidine's effects, both of which were abolished by intracisternal SB\u2010334867, an orexin 1 receptor antagonist. Furthermore, atropine, sulpiride, and N\n                      <jats:sup>G<\/jats:sup>\n                      \u2010nitro\u2010L\u2010arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, but not scopolamine butylbromide, a peripheral muscarinic receptor antagonist, or domperidone, a peripheral dopamine D\n                      <jats:sub>2<\/jats:sub>\n                      receptor antagonist, blocked cimetidine's action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings suggest that cimetidine prevents visceral hypersensitivity and colonic hyperpermeability in IBS models through mechanisms involving central orexin signaling possibly triggered by NHE inhibition, NO, and central muscarinic and dopamine D\n                      <jats:sub>2<\/jats:sub>\n                      receptor pathways. These findings may provide a basis for future therapeutic approaches targeting IBS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/fcp.70091","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T06:48:04Z","timestamp":1777963684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing Cimetidine as a Therapeutic Candidate for Irritable Bowel Syndrome in a Rat Model"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4225-2575","authenticated-orcid":false,"given":"Tsukasa","family":"Nozu","sequence":"first","affiliation":[{"name":"Department of Regional Medicine and Education Asahikawa Medical University  Asahikawa Hokkaido Japan"},{"name":"Center for Medical Education Asahikawa Medical University  Asahikawa Hokkaido Japan"},{"name":"Department of General Medicine Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Miyagishi","sequence":"additional","affiliation":[{"name":"Department of General Medicine Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatomo","family":"Ishioh","sequence":"additional","affiliation":[{"name":"Department of General Medicine Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Takakusaki","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Physiology Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1810-007X","authenticated-orcid":false,"given":"Toshikatsu","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of General Medicine Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i39.14126"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102022\u2010328515"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.151.373"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.5056\/jnm16001"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535\u2010015\u20101086\u20108"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014\u20101421"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535\u2010006\u20101848\u20104"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.42.6.845"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12670"},{"issue":"12","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"711","DOI":"10.4321\/S1130-01082010001200006","article-title":"Irritable Bowel Syndrome Immune Hypothesis. 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