Selective role for TRPV4 ion channels in visceral sensory pathways.
OBJECTIVE
Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4).


METHODS
We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors.


RESULTS
Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4.


CONCLUSIONS
These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments.
Brierley
Stuart M
SM
Discipline of Physiology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, Australia.
Page
Amanda J
AJ
Hughes
Patrick A
PA
Adam
Birgit
B
Liebregts
Tobias
T
Cooper
Nicole J
NJ
Holtmann
Gerald
G
Liedtke
Wolfgang
W
Blackshaw
L Ashley
LA
D000344:Afferent Pathways / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002404:Catheterization; D003106:Colon / Q000294:innervation*; D017615:Enteric Nervous System / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008465:Mechanoreceptors / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009475:Neurons, Afferent / Q000378:metabolism; D010146:Pain / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold; D012333:RNA, Messenger / Q000378:metabolism; D012677:Sensation; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; D015740:Calcitonin Gene-Related Peptide