Selective Role for TRPV4 Ion Channels in Visceral Sensory Pathways

doi:10.1053/j.gastro.2008.01.074

Gastroenterology

Volume 134, Issue 7, June 2008, Pages 2059-2069

https://doi.org/10.1053/j.gastro.2008.01.074 Get rights and content

Background & Aims: 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.

Section snippets

Materials and Methods

All experiments were approved by the Animal Ethics Committees of the Institute of Veterinary Science and the University of Adelaide and by the human ethics committee of the Royal Adelaide Hospital.

Expression of TRPV4 in Visceral Afferent Pathways

Using a combination of techniques that we have recently developed for assessing molecular expression in identified neuronal populations,13, 14 we investigated expression of TRPV4 in visceral and nonvisceral sensory neurons. A small proportion of neurons in sensory ganglia were retrogradely labeled from stomach or colon: 5.0% ± 0.7% of nodose ganglion neurons from stomach, 2.9% ± 0.1% in thoracolumbar DRG, and 2.3% ± 0.2% in lumbosacral DRG from colon. Fluorescence in situ hybridization combined

Discussion

This study provides anatomical, molecular, and functional evidence for a specialized role of TRPV4 in a subpopulation of colonic mechanoreceptors; it extends functional evidence into behavior of the whole animal and anatomical evidence into observations of human tissue. These findings indicate a molecular specialization of sensory neurons from the viscera.

Distinct populations of colonic mechanoreceptors exist which have high thresholds to mechanical stimulation that project centrally in the

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: Supported by the National Health and Medical Research Council of Australia Project Grant and Senior Research Fellowship, NIH project grant, Glaxo SmithKline Young Investigator Award, and the University of Adelaide Postgraduate Scholarship.

: Stuart M. Brierley, Amanda J. Page, and Patrick A. Hughes contributed equally to this work.

: All authors declare that they have no conflict of interest to disclose.

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Basic–Alimentary TractSelective Role for TRPV4 Ion Channels in Visceral Sensory Pathways

Section snippets

Materials and Methods

Expression of TRPV4 in Visceral Afferent Pathways

Discussion

Pain

Gastroenterology

Gastroenterology

Curr Opin Pharmacol

Cell

Neuron

Neurosci Lett

Pain

Am J Gastroenterol

Pain

Gastroenterology

Am J Gastroenterol

J Biol Chem

Neuroscience

Basic–Alimentary Tract
Selective Role for TRPV4 Ion Channels in Visceral Sensory Pathways