{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:57:05Z","timestamp":1790517425614,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T00:00:00Z","timestamp":1527120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010721","name":"Ironwood Pharmaceuticals, Incorporated","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010721","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Irritable bowel syndrome (<jats:styled-content style=\"fixed-case\">IBS<\/jats:styled-content>) and bladder pain syndrome (<jats:styled-content style=\"fixed-case\">BPS<\/jats:styled-content>) are female\u2010predominant, chronic functional pain disorders that are associated with early life stress (<jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content>) and therapeutic options for such patients remain limited. Linaclotide, a guanylate cyclase\u2010C (<jats:styled-content style=\"fixed-case\">GC<\/jats:styled-content>\u2010C) agonist, relieves abdominal pain and bowel symptoms in adult patients suffering from <jats:styled-content style=\"fixed-case\">IBS<\/jats:styled-content> with constipation. Here, we test the hypothesis that linaclotide will reverse colon and bladder hyperalgesia in a female\u2010specific rodent model of adverse early life experience.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neonatal rats were exposed to an odor\u2010attachment learning paradigm of early life stress (<jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content>). In adulthood, the effect of linaclotide (3\u00a0\u03bcg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0d<jats:sup>\u22121<\/jats:sup>, p.o.) on colonic and bladder sensitivity was assessed via quantification of the visceromotor response to colorectal distension and the frequency of withdrawal responses to the application of von Frey hairs to the suprapubic region. In another cohort of rats, the effect of linaclotide on <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content>\u2010induced colonic and bladder permeability was investigated via measurements of transepithelial electrical resistance (<jats:styled-content style=\"fixed-case\">TEER<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Rats exposed to unpredictable <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> exhibited colonic and bladder hypersensitivity that was significantly reduced by linaclotide compared to vehicle\u2010treated controls. Colonic and bladder tissue isolated from adult rats exposed to unpredictable <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> exhibited a decrease in colonic and bladder <jats:styled-content style=\"fixed-case\">TEER<\/jats:styled-content> that was reversed by linaclotide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Inferences<\/jats:title><jats:p>Our results demonstrate that neonatal rats exposed to unpredictable <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> develop increased sensitivity and permeability of the colon and bladder in adulthood through a mechanism involving activation of peripheral <jats:styled-content style=\"fixed-case\">GC<\/jats:styled-content>\u2010C signaling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.13375","type":"journal-article","created":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T08:02:11Z","timestamp":1527148931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-1477","authenticated-orcid":false,"given":"C.","family":"Ligon","sequence":"first","affiliation":[{"name":"Oklahoma Center for Neuroscience University of Oklahoma Health Sciences Center  Oklahoma City OK USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Oklahoma Center for Neuroscience University of Oklahoma Health Sciences Center  Oklahoma City OK USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Ge","sequence":"additional","affiliation":[{"name":"Ironwood Pharmaceuticals  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Hannig","sequence":"additional","affiliation":[{"name":"Ironwood Pharmaceuticals  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Higgins","sequence":"additional","affiliation":[{"name":"Ironwood Pharmaceuticals  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2647-1316","authenticated-orcid":false,"given":"B.","family":"Greenwood\u2010Van Meerveld","sequence":"additional","affiliation":[{"name":"Oklahoma Center for Neuroscience University of Oklahoma Health Sciences Center  Oklahoma City OK USA"},{"name":"Department of Physiology University of Oklahoma Health Sciences Center  Oklahoma City OK USA"},{"name":"Department of Veterans Affairs University of Oklahoma Health Sciences Center  Oklahoma City OK USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.11.061"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gtc.2005.02.011"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2002.05913.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2010.06.005"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-017-4364-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4471-3293-6_4"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00395.2005"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.5489\/cuaj.11110"},{"issue":"2","key":"e_1_2_9_10_1","first-page":"S40","article-title":"Childhood abuse is not only a case of bruises and broken bones: role of abuse in unexplained GI symptoms in children","volume":"53","author":"Tilburg M","year":"2011","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2011.12.018"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00042737-199704000-00002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-016-0062-1"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12472"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2012.11.008"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00240.2001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.37095"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2006.10.010"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2013.12.041"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2012.255"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2012.254"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90497-3"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.01.003"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2010.03.015"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.09.019"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2009.01385.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.08.041"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.08.017"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016139"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(16)30506-6"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2007.00955.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-016-0082-x"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12891"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2015.16"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(01)00275-5"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2014.11.045"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002210"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.05907"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-129-5-2503"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(90)90332-U"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(91)90717-Y"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.472715"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/dev.420210103"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1037\/0735-7044.114.5.957"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.02.039"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2013.00013"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e318264e918"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.06.017"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0b013e3182802a4e"}],"container-title":["Neurogastroenterology &amp; Motility"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fnmo.13375","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nmo.13375","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/nmo.13375","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nmo.13375","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T15:36:34Z","timestamp":1694100994000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/nmo.13375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,24]]},"references-count":48,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1111\/nmo.13375"],"URL":"https:\/\/doi.org\/10.1111\/nmo.13375","archive":["Portico"],"relation":{},"ISSN":["1350-1925","1365-2982"],"issn-type":[{"value":"1350-1925","type":"print"},{"value":"1365-2982","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,24]]},"assertion":[{"value":"2018-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13375"}}