The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli.
OBJECTIVE
The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRP ankyrin 1 (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 whose neurons innnervate 3 different regions of the GI tract were analyzed from wild-type and TRPA1(-/-) mice using quantitative reverse-transcription polymerase chain reaction, 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-activated receptor-2 and TRPA1 was evident.


CONCLUSIONS
These findings demonstrate a previously unrecognized role for TRPA1 in normal and inflamed mechanosensory function and nociception within the viscera.
Brierley
Stuart M
SM
Nerve-Gut Research Laboratory, Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Hughes
Patrick A
PA
Page
Amanda J
AJ
Kwan
Kelvin Y
KY
Martin
Christopher M
CM
O'Donnell
Tracey A
TA
Cooper
Nicole J
NJ
Harrington
Andrea M
AM
Adam
Birgit
B
Liebregts
Tobias
T
Holtmann
Gerald
G
Corey
David P
DP
Rychkov
Grigori Y
GY
Blackshaw
L Ashley
LA
D000200:Action Potentials; D000344:Afferent Pathways / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056347:Neuroanatomical Tract-Tracing Techniques; D009620:Nodose Ganglion / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D010388:Pelvis / Q000294:innervation; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013153:Splanchnic Nerves / Q000378:metabolism / Q000503:physiopathology; D013268:Stimulation, Chemical; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid
D012333:RNA, Messenger; D044464:Receptor, PAR-2; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D014302:Trinitrobenzenesulfonic Acid; D002211:Capsaicin; D001920:Bradykinin