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TRP channels as therapeutic targets in IBS 85 4 Accumulating evidence points toward a role of TRPV4 in mechanosensation. 3,41 Under basal conditions, TRPV4 is thought to primarily sense high threshold mechanical stimuli. 42 Comparing TRPV4 knockout and wildtype mice, responses to noxious distension pressures were diminished in TRPV4 knockouts. In contrast, responses did not differ at innocuous pressures. TRPV4 is however considered to play a major role in visceral hypersensitivity. 42,43 Intracolonic administration of 4 PDD has been shown to induce hyperalgesia in mice. 42 In IBS, several pathways have been proposed to result in visceral hypersensitivity through TRPV4 sensitization. The effects on TRPV4 of known mediators of visceral hypersensitivity, serotonin and histamine, were investigated in one study. 44 Serotonin and histamine administration was demonstrated to result in potentiated TRPV4 responses to 4 PDD. The same research group postulated a role for proteases in mediating visceral hypersensitivity. 45 Subsequent studies have supported this theory. 42,43 Activation of Protease-Activated Receptor (PAR 2 ), a channel that is also co-expressed with TRPV4 in afferents innervating the colon, resulted in visceral hyperalgesia in wildtype mice. Because hyperalgesia was lacking in TRPV4 knockout mice, this channel was suspected to be the downstream effector of PAR 2 mediated visceral hypersensitivity. 42 Human studies on visceral TRPV4 functioning are currently limited. In one study researchers acquired supernatant of colonic biopsies from IBS-D patients. 31 Intracolonic administration of the supernatant resulted in visceral hypersensitivity in mice. This was concluded to be TRPV4 mediated, as injection of TRPV4 targeted small interfering RNA prevented the effect. Subsequently, potential TRPV4 agonists in the supernatant were quantified. The concentration of 5,6-EET was found to be significantly elevated and correlated with patients’ abdominal pain severity and frequency. Interestingly, 5,6-EET production was linked to PAR 2 activation, as PAR 2 agonist peptide induced 5,6-EET synthesis in sensory neurons. The authors therefore suggested 5,6-EET to be an endogenous TRPV4 agonist with a major role in visceral hypersensitivity in IBS-D patients. Again, the heterogeneity of IBS should be emphasised as the above solely relates to IBS-D patients. No significant differences in poly-unsaturated fatty acid metabolite concentrations in supernatants have been observed in constipation predominant IBS (IBS-C) patients, mixed bowel habit IBS (IBS-M) patients and healthy volunteers. TRPA1 To date, our knowledge on Transient Receptor Potential Ankyrin 1 (TRPA1) functions in visceral nociception is mostly limited to animal models. TRPA1 is thought to primarily