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We previously identified that synaptic plasticity of enteric nerve system (ENS) contributed to peripheral pain maintaining in the gut. However, the mechanisms of enteric \u201cmemory\u201d formation remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, rats were exposed to water avoidance stress (WAS) or sham stress (SS), with cromolyn sodium or physiological saline injected intraperitoneally 30\u00a0minutes before stress every day. The abdominal withdrawal reflex scores, mesenteric afferent nerve activity, enteric neural <jats:italic>c\u2010fos<\/jats:italic> expression, and enteric synaptic plasticity were assessed, and mast cell infiltration and degranulation. Furthermore, colonic mucosal mediators\u2010induced enteric synaptic plasticity and the role of mast cell\u2010derived nerve growth factor (NGF), tryptase, and histamine were investigated via ex vivo longitudinal muscle\u2010myenteric plexus (LMMP) organotypic culture.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>It is shown that mast cell stabilizing inhibited WAS\u2010induced visceral hypersensitivity through enhancing visceral pain threshold, decreasing spontaneous and distention\u2010induced mesenteric afferent firing, and downregulating enteric neural activation (<jats:italic>c\u2010fos<\/jats:italic>). Importantly, WAS led to evident enteric synaptic plasticity, but decreased by cromolyn. Water avoidance stress\u2010derived mucosal supernatants markedly enhanced the <jats:italic>c\u2010fos<\/jats:italic> expression and enteric synaptic plasticity in LMMP tissues, which could be eliminated by mast cell inhibition or NGF neutralization, but not tryptase or histamine blocking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>In conclusion, mast cells\/NGF pathway may be the key regulator of synaptic plasticity of ENS and participate in the formation of chronic stress\u2010induced sustained visceral hypersensitivity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.13430","type":"journal-article","created":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T13:03:17Z","timestamp":1533301397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Sustained pain hypersensitivity in the stressed colon: Role of mast cell\u2010derived nerve growth factor\u2010mediated enteric synaptic plasticity"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4921-8986","authenticated-orcid":false,"given":"L.","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Bai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan 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