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      TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis.

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          Abstract

          Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild-type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1-deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation.

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          Author and article information

          Journal
          Am. J. Physiol. Gastrointest. Liver Physiol.
          American journal of physiology. Gastrointestinal and liver physiology
          American Physiological Society
          1522-1547
          0193-1857
          Jul 15 2015
          : 309
          : 2
          Affiliations
          [1 ] Department of Physiology and Pharmacology, Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada;
          [2 ] Institut National de la Santé et de la Recherche Medicale (INSERM), Toulouse, France; Le Centre National de la Recherche Scientifique (CNRS), Toulouse, France; and Université de Toulouse III Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
          [3 ] Department of Physiology and Pharmacology, Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada; Institut National de la Santé et de la Recherche Medicale (INSERM), Toulouse, France; Le Centre National de la Recherche Scientifique (CNRS), Toulouse, France; and Université de Toulouse III Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
          [4 ] Department of Physiology and Pharmacology, Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada; altier@ucalgary.ca.
          Article
          ajpgi.00421.2014
          10.1152/ajpgi.00421.2014
          26021808
          42a96ba1-928d-4ab0-b9e4-06ec61976b52
          History

          inflammatory bowel disease,peripheral sensitization,substance P,transient receptor potential vanilloid 1,visceral pain

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