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

Abstract

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. TRPV4 expression was investigated by immunohistochemistry and reverse transcription-polymerase chain reaction. Calcium signaling and patch-clamp studies were performed in dorsal root ganglia (DRG) neurons validating the use of 4alphaPDD as a selective TRPV4 agonist. The effects of TRPV4 activation on visceral nociception were evaluated in mice that received intracolonically TRPV4 agonist (4 alpha-phorbol 12,13-didecanoate [4alphaPDD]) and in TRPV4-deficient mice in which abdominal muscle contractions in response 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 (PAR(2)) activation-induced visceral hypersensitivity. TRPV4 agonist 4alphaPDD specifically activated a cationic current and calcium influx in colonic projections of DRG neurons and caused dose-dependent visceral hypersensitivity. TRPV4-targeted but not mismatched siRNA intervertebral treatments were effective at reducing basal visceral nociception, as well as 4alphaPDD or PAR(2) agonist-induced hypersensitivity. Effects of the TRPV4 ligand were lost in TRPV4-deficient mice. 4alphaPDD selectively activates TRPV4 in sensory neurons projecting from the colon, and TRPV4 activation causes visceral hypersensitivity. TRPV4 activation is implicated in the nociceptive response to CRD in basal conditions and in PAR(2) agonist-induced hypersensitivity. These results suggest a pivotal role for TRPV4 in visceral nociception and hypersensitivity.