The Ion Channel TRPA1 Is Required for Normal Mechanosensation and Is Modulated by Algesic Stimuli

Abstract

Background & Aims The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRPA1 is implicated in inflammatory pain; it interacts with G-protein-coupled receptors, but little is known about its role in the gastrointestinal (GI) tract. Sensory information from the GI tract is conducted via 5 afferent subtypes along 3 pathways. Methods Nodose and dorsal root ganglia (DRG) whose neurons innnervate 3 different regions of the GI tract were analyzed from wild-type and TRPA1−/− mice using quantitative RT-PCR, retrograde labeling, and in situ hybridization. Distal colon sections were analyzed by immunohistochemistry. In vitro electrophysiology and pharmacology studies were performed and colorectal distension and visceromotor responses were measured. Colitis was induced by administration of trinitrobenzene sulphonic acid. Results TRPA1 is required for normal mechano- and chemosensory function in specific subsets of vagal, splanchnic and pelvic afferents. The behavioral responses to noxious colonic distension were substantially reduced in TRPA1−/− mice. TRPA1 agonists caused mechanical hypersensitivity, which increased in mice with colitis. Colonic afferents were activated by bradykinin and capsaicin, which mimic effects of tissue damage; wild-type and TRPA1 −/− mice had similar direct responses to these 2 stimuli. After activation by bradykinin, wild-type afferents had increased mechanosensitivity whereas after capsaicin exposure, mechanosensitivity was reduced—these changes were absent in TRPA1−/− mice. No interaction between protease receptor (2) activation and TRPA1 was evident. Conclusion These findings demonstrate a previously unrecognized role for TRPA1 in normal and inflamed mechanosensory function and nociception within the viscera.