Journal Club 18.03.23.

Transient Receptor Potential Vanilloid-4 Has a Major Role in Visceral Hypersensitivity Symptoms

TRPV4 ROLE IN VISCERAL HYPERSENSITIVITY

NICOLAS CENAC,*,‡,§ CHRISTOPHE ALTIER,* KEVIN CHAPMAN,* WOLFGANG LIEDTKE, GERALD ZAMPONI,* and NATHALIE VERGNOLLE*,‡,§
*Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada; ‡INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; §Université Toulouse III Paul Sabatier, Toulouse, France; and Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina

Background & Aims: The transient receptor potential vanilloid-4 (TRPV4) is an osmosensitive channel that responds to mechanical stimulation. We hypothesized that TRPV4 could be important in visceral nociception and in the development of hypersensitivity. Methods: TRPV4 expression was investigated by immunohis- tochemistry and reverse transcription–polymerase chain reaction. Calcium signaling and patch-clamp studies were performed in dorsal root ganglia (DRG) neurons validating the use of 4 PDD as a selective TRPV4 agonist. The effects of TRPV4 activation on visceral nociception were evaluated in mice that re- ceived intracolonically TRPV4 agonist (4 -phorbol 12,13-didecanoate [4 PDD]) and in TRPV4-deficient mice in which abdominal muscle contractions in re- sponse to colorectal distention (CRD) were recorded. Intervertebral injections of TRPV4 or mismatch small interfering RNA (siRNA) were used to specifically down-regulate TRPV4 expression in sensory neurons and to investigate the role of TRPV4 in basal visceral nociception or in protease-activated receptor 2 (PAR2) activation-induced visceral hypersensitivity. Results: TRPV4 agonist 4 PDD specifically activated a cat- ionic current and calcium influx in colonic projec- tions of DRG neurons and caused dose-dependent visceral hypersensitivity. TRPV4-targeted but not mismatched siRNA intervertebral treatments were ef- fective at reducing basal visceral nociception, as well as 4 PDD or PAR2 agonist-induced hypersensitivity. Effects of the TRPV4 ligand were lost in TRPV4- deficient mice. Conclusions: 4 PDD selectively acti- vates TRPV4 in sensory neurons projecting from the colon, and TRPV4 activation causes visceral hypersen- sitivity. TRPV4 activation is implicated in the nocicep- tive response to CRD in basal conditions and in PAR2 agonist-induced hypersensitivity. These results suggest a pivotal role for TRPV4 in visceral nociception and hypersensitivity.