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TRP channels as therapeutic targets in IBS 87 4 TRPA1 itself is undoubtedly affected by inflammatory mediators. Indeed, the endogenous agonists of TRPA1 are related to inflammation (see Table 4.2 ). Furthermore, studies investigating the effects of chemically induced colitis in mice demonstrated sensitization of visceral afferents to mechanical stimuli. These effects were observed in wildtype mice, but not in TRPA1 deficient mice. 47,53,54 Since TRPV1, TRPV4 and TRPA1 have all been shown to be involved in inflammation induced visceral hyperalgesia, one could assume that combined sensitization of these channels provides a particularly potent mechanism to induce hypersensitivity. Synergistic effects of TRPV1 and TRPA1 inhibition have indeed been demonstrated in the attenuation of colorectal distension-associated pain behaviour at high pressures in rats. 54 Unfortunately, this concept has not yet been proven in IBS. Cenac et al . have measured endogenous agonists of TRPA1, TRPV1 and TRPV4 (primarily inflammatory mediators) in the supernatant of colon biopsy material of IBS patients. 31 They demonstrated elevated levels of endogenous agonists of TRPV4, but not TRPA1 or TRPV1. Another study involved peripheral blood mononuclear cell supernatants from IBS-D patients. 55 The supernatants were shown to induce mechanical hypersensitivity in vitro in colonic afferent neurons. Cytokine concentrations in the supernatants were subsequently measured, showing elevated levels of TNF- , soluble IL-2, IL-6, IL-10, IL-1 and the chemokines CCL3 and CCL4. Combined with the expression profiles of the receptors of these signalling molecules in colonic nerves, the authors proposed TNF- , IL-6, IL-10 and IL-1 as possible mediators of mechanical hypersensitivity in IBD-D. The mechanism of action of TNF- was demonstrated to be TRPA1 dependent, as its sensitizing effect was abolished in the presence of a TRPA1 antagonist. In contrast, the selective inhibition of TRPV1 using low doses of capsazepine had no effects on mechanical hypersensitivity induced by TNF- . In addition, a more recent study by the same group demonstrated IL- 6 mediated mechanical hypersensitivity to be TRPA1 dependent as well. 56 Whether an interaction of sensitized TRP channels plays an important role in IBS thus remains to be elucidated. Future studies should include different approaches covering the diversity of potential pathophysiological mechanisms in IBS. For example, elevated levels of hydrogen sulphide, an endogenous TRPA1 agonist, were recently demonstrated in IBS-D patients with small bacterial overgrowth. 57 These findings demonstrate that mechanisms of TRP channel sensitization may vary among patients.