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      TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus.

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          Abstract

          Sensitization of esophageal sensory afferents by inflammatory mediators plays an important role in esophageal nociception. We have shown esophageal mast cell activation induces long-lasting mechanical hypersensitivity in vagal nodose C-fibers. However, the roles of mast cell mediators and downstream ion channels in this process are unclear. Mast cell tryptase via protease-activated receptor 2 (PAR2)-mediated pathways sensitizes sensory nerves and induces hyperalgesia. Transient receptor potential A1 (TRPA1) plays an important role in mechanosensory transduction and nociception. Here we tested the hypothesis that mast cell activation via a PAR2-dependent mechanism sensitizes TRPA1 to induce mechanical hypersensitivity in esophageal vagal C-fibers. The expression profiles of PAR2 and TRPA1 in vagal nodose ganglia were determined by immunostaining, Western blot, and RT-PCR. Extracellular recordings from esophageal nodose neurons were performed in ex vivo guinea pig esophageal-vagal preparations. Action potentials evoked by esophageal distention and chemical perfusion were compared. Both PAR2 and TRPA1 expressions were identified in vagal nodose neurons by immunostaining, Western blot, and RT-PCR. Ninety-one percent of TRPA1-positive neurons were of small and medium diameters, and 80% coexpressed PAR2. Esophageal mast cell activation significantly enhanced the response of nodose C-fibers to esophageal distension (mechanical hypersensitivity). This was mimicked by PAR2-activating peptide, which sustained for 90 min after wash, but not by PAR2 reverse peptide. TRPA1 inhibitor HC-030031 pretreatment significantly inhibited mechanical hypersensitivity induced by either mast cell activation or PAR2 agonist. Collectively, our data provide new evidence that sensitizing TRPA1 via a PAR2-dependent mechanism plays an important role in mast cell activation-induced mechanical hypersensitivity of vagal nodose C-fibers in guinea pig esophagus.

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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 2009
          : 297
          : 1
          Affiliations
          [1 ] Division of Gastroenterology and Hepatology, The Milton S. Hershey Medical Center, Penn State University College of Medicine, 500 Univ. Drive, Hershey, PA 17033, USA. suy13@psu.edu
          Article
          00068.2009
          10.1152/ajpgi.00068.2009
          19423751
          6b01b717-7b8c-49c2-b3b6-00935082fbf1
          History

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