{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:42:36Z","timestamp":1768509756554,"version":"3.49.0"},"posted":{"date-parts":[[2023,12,19]]},"group-title":"Genetics","reference-count":67,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI\/IBS. Comparing two C57BL\/6 (BL\/6) substrains (C57BL\/6NTac and C57BL\/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan (ZYM) instillation, a validated preclinical model for post-inflammatory IBS. Using whole genome sequencing, we identified a SNP differentiating the two strains in the 5\u2019 intergenic region upstream of\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  , encoding the protein arginine-vasopressin receptor 1A (AVPR1A). We used behavioral, histological, and molecular approaches to identify distal colon- specific gene expression differences and neuronal hyperresponsiveness covarying with\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  genotype and VH susceptibility. While the two BL\/6 substrains did not differ across other gastrointestinal (GI) phenotypes (e.g., GI motility), VH-susceptible BL\/6NTac mice had higher colonic\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  mRNA and protein expression. Moreover, neurons of the enteric nervous system were hyperresponsive to the AVPR1A agonist AVP, suggesting a role for enteric neurons in the pathology underlying VH. These results parallel our findings that patients\u2019 colonic\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  mRNA expression was higher in patients with higher pain ratings. Taken together, these findings implicate differential regulation of\n                  <jats:italic>Avpr1a<\/jats:italic>\n                  as a novel mechanism of VH-susceptibility as well as a potential therapeutic target specific to VH.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    A combination of approaches, from genomic analysis to functional analyses, confirm\n                    <jats:italic>Avpr1a<\/jats:italic>\n                    as a high priority candidate gene for visceral pain.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.12.19.572390","type":"posted-content","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T02:35:22Z","timestamp":1703039722000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of arginine-vasopressin receptor 1a (Avpr1a\/AVPR1A) as a novel candidate gene for chronic visceral pain"],"prefix":"10.64898","author":[{"given":"Leena","family":"Kader","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Willits","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Meriano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-5192","authenticated-orcid":false,"given":"Julie A.","family":"Christianson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Ho","family":"La","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9277-211X","authenticated-orcid":false,"given":"Bin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittany","family":"Knight","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gulum","family":"Kosova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Deberry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Coates","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Hyams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0437-9209","authenticated-orcid":false,"given":"Kyle","family":"Baumbauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin E.","family":"Young","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023122211000918000_2023.12.19.572390v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(94)90086-8"},{"key":"2023122211000918000_2023.12.19.572390v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0889-8553(05)70374-5"},{"key":"2023122211000918000_2023.12.19.572390v1.3","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.1.125"},{"key":"2023122211000918000_2023.12.19.572390v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2004.02160.x"},{"issue":"6","key":"2023122211000918000_2023.12.19.572390v1.5","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/apt.14503","article-title":"Opioid medication use in patients with gastrointestinal diagnoses vs unexplained gastrointestinal symptoms in the US Veterans Health Administration","volume":"47","year":"2018","journal-title":"Aliment Pharmacol Ther"},{"key":"2023122211000918000_2023.12.19.572390v1.6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jsat.2017.03.006","article-title":"Chronic pain among patients with opioid use disorder: Results from electronic health records data","volume":"77","year":"2017","journal-title":"J Subst Abuse Treat"},{"key":"2023122211000918000_2023.12.19.572390v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2011.83"},{"key":"2023122211000918000_2023.12.19.572390v1.8","doi-asserted-by":"crossref","unstructured":"Azpiroz, F. , et al., Mechanisms of hypersensitivity in IBS and functional disorders. 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