{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:43:13Z","timestamp":1790815393233,"version":"4.1.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T00:00:00Z","timestamp":1571270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council of Australia","award":["NHMRC R.D Wright Biomedical Research Fellow (APP1126378 to S.M.B)"],"award-info":[{"award-number":["NHMRC R.D Wright Biomedical Research Fellow (APP1126378 to S.M.B)"]}]},{"name":"National Health and Medical Research Council of Australia","award":["Project Grant #1083480 (to S.M.B"],"award-info":[{"award-number":["Project Grant #1083480 (to S.M.B"]}]},{"name":"National Health and Medical Research Council of Australia","award":["D.P.P)"],"award-info":[{"award-number":["D.P.P)"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS102722,DE026806,DK118971,to NWB"],"award-info":[{"award-number":["NS102722,DE026806,DK118971,to NWB"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"United States Department of Defence","award":["W81XWH1810431,to NWB"],"award-info":[{"award-number":["W81XWH1810431,to NWB"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,17]]},"abstract":"<jats:p>\n                    Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. While pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors\n                    <jats:italic>Tgr5<\/jats:italic>\n                    and the Mas-gene\u2013related GPCRs\n                    <jats:italic>Mrgpra3<\/jats:italic>\n                    and\n                    <jats:italic>Mrgprc11<\/jats:italic>\n                    . Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intracolonic administration of individual TGR5, MrgprA3, or MrgprC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Coadministration of these agonists as an \u201citch cocktail\u201d augmented hypersensitivity to colorectal distension and changed mouse behavior. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed\n                    <jats:italic>TGR5<\/jats:italic>\n                    , as well as the human ortholog\n                    <jats:italic>MrgprX1<\/jats:italic>\n                    , and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.131712","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T12:01:41Z","timestamp":1568894501000},"source":"Crossref","is-referenced-by-count":80,"title":["Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity"],"prefix":"10.1172","volume":"4","author":[{"given":"Joel","family":"Castro","sequence":"first","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-4137","authenticated-orcid":true,"given":"Andrea M.","family":"Harrington","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TinaMarie","family":"Lieu","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5038-0820","authenticated-orcid":true,"given":"Sonia","family":"Garcia-Caraballo","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Maddern","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Schober","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3900-7141","authenticated-orcid":true,"given":"Luke","family":"Grundy","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-6498","authenticated-orcid":true,"given":"Amanda L.","family":"Lumsden","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Miller","sequence":"additional","affiliation":[{"name":"AnaBios Corporation, San Diego, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Ghetti","sequence":"additional","affiliation":[{"name":"AnaBios Corporation, San Diego, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Steinhoff","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Dermatology Immunology Institute, Hamad Medical Corporation, Doha, Qatar."},{"name":"Department of Dermatology, Weill Cornell Medicine-Qatar and Weill Cornell University, New York, New York, USA."},{"name":"School of Medicine Qatar University, Doha, Qatar."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6168-8422","authenticated-orcid":true,"given":"Daniel P.","family":"Poole","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia."},{"name":"Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia."},{"name":"Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhong","family":"Dong","sequence":"additional","affiliation":[{"name":"The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6800-2967","authenticated-orcid":true,"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"G. Oppenheimer Centre for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3367-0644","authenticated-orcid":true,"given":"Nigel W.","family":"Bunnett","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia."},{"name":"Department of Surgery and"},{"name":"Department of Pharmacology, Columbia University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2527-2905","authenticated-orcid":true,"given":"Stuart M.","family":"Brierley","sequence":"additional","affiliation":[{"name":"Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia."},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia."},{"name":"Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,10,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30217-5"},{"key":"B2"},{"issue":"181","key":"B3","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2001925","article-title":"The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia","volume":"4","author":"Liu","year":"2011","journal-title":"Sci Signal"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233765"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3641"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64551"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00483-4"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.034"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2789"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.08.042"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2018.02.017"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.12.034"},{"issue":"3","key":"B13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.5009\/gnl14397","article-title":"Bile Acid diarrhea: prevalence, pathogenesis, and therapy","volume":"9","author":"Camilleri","year":"2015","journal-title":"Gut Liver"},{"key":"B14","unstructured":"NIH USNLoMMP. Chloroquine. https:\/\/medlineplus.gov\/druginfo\/meds\/a682318.html 2017;https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/006002s044lbl.pdf Last Revised - 06\/15\/2017. Accessed: 03\/02\/2019"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2016.14","article-title":"Irritable bowel syndrome","volume":"2","author":"Enck","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2014.103"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.0954"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2008.01997.x"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.023"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5161-13.2014"},{"issue":"Pt 14","key":"B21","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.1113\/jphysiol.2011.206789","article-title":"TRPA1 contributes to specific mechanically activated currents and sensory neuron mechanical hypersensitivity","volume":"589","author":"Brierley","year":"2011","journal-title":"J Physiol (Lond)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.07.048"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-301856"},{"issue":"Pt 1","key":"B24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1113\/jphysiol.2005.089714","article-title":"Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice","volume":"567","author":"Brierley","year":"2005","journal-title":"J Physiol (Lond)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310971"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.08.017"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms4165","article-title":"Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain","volume":"5","author":"de Araujo","year":"2014","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001368"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001453"},{"issue":"19","key":"B30","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.121841","article-title":"Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction","volume":"3","author":"Grundy","year":"2018","journal-title":"JCI Insight"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23042"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00013.2019"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201600297"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14115"},{"issue":"11","key":"B35","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.121000","article-title":"NaV1.1 inhibition can reduce visceral hypersensitivity","volume":"3","author":"Salvatierra","year":"2018","journal-title":"JCI Insight"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2009.05248.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.170811"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature17976"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-020518-114525"},{"issue":"8","key":"B40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/nmo.13623","article-title":"Mas-related G protein-coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?","volume":"31","author":"Van Remoortel","year":"2019","journal-title":"Neurogastroenterol Motil"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.09.055"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025637"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00016.2019"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature06029"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4918"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00221.2009"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2009.192567"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1136\/gut.18.8.606"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nn815"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2007.11.004"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00121.2015"},{"issue":"8656","key":"B52","doi-asserted-by":"crossref","DOI":"10.1016\/S0140-6736(89)90391-7","article-title":"Pruritus and antimalarial drugs in Africans","volume":"2","author":"Sowunmi","year":"1989","journal-title":"Lancet"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1192-11.2011"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.sder.2011.04.009"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aal2171"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0074-8"},{"key":"B57","doi-asserted-by":"crossref","DOI":"10.1038\/srep42810","article-title":"Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1","volume":"7","author":"Inserra","year":"2017","journal-title":"Sci Rep"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/131712\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:22:50Z","timestamp":1779193370000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/131712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,17]]},"references-count":57,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10,17]]},"published-print":{"date-parts":[[2019,10,17]]}},"alternative-id":["10.1172\/jci.insight.131712"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.131712","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,17]]},"article-number":"e131712"}}