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Chapter 4 90 activation on motility are not only channel dependent, but also location dependent. For example, TRPV1-positive fibres located in the lower oesophageal sphincter that are exposed to gastric acid cause a local inhibitory reflex, lowering the intraluminal pressure. 75 On the other hand, application of capsaicin in the distal colon and rectum in mice has been shown to cause fast transient colonic contractions followed by a delayed sustained contraction. 76 These results indicate that different effector pathways are involved depending on the location. Suggested effectors are the tachykinin receptors (mainly NK1 and NK2), which respond to neuropeptides released upon TRP channel activation, as discussed above. 77 Indeed, the contractility lowering effect in the oesophagus was demonstrated to be NK1 dependent via local substance P release, whereas NK2 activation was shown to be responsible for long lasting contractility in the distal colon. 75,76 Additional pathways are likely to be involved however, as fast transient colonic contractions were shown to be inhibited by NK1 antagonists. Other TRP channels have also been implicated in motility. Whereas TRPV4 has previously been demonstrated to inhibit colonic motility in mice via reduced NO-dependent calcium release, TRPA1 has been implicated in both reduced and increased motor activity. 39,78,79 Taken together, the effects on gut motility emphasise the involvement of TRP channels in IBS pathophysiology, as they may account for both the altered defecation pattern as well as pain symptoms encountered in the syndrome. Clinical implications Although all of the TRP channels discussed above are suggested to have a role in visceral pain generation, only two (TRPV1 and TRPM8) have been implied in the treatment of IBS. Generally, two strategies are exploited in blocking TRP channels. One is the direct inhibition by administration of antagonists, the other one by repeated stimulation in order to desensitize the channel and its respective nerve terminal. In addition, several alternative techniques for TRP channel targeted therapy have been developed, that will be discussed hereafter. A summary of the optional therapeutic strategies related to each TRP channel is provided in Table 4.3 . TRP antagonists The discovery of TRPV1 as a key player in nociception led to the development of TRPV1 antagonists as novel therapeutics in pain control. However, investigators soon encountered a major hurdle, as the first compounds interfered with thermoregulation. Several first-generation compounds were stranded in pre-clinical trials as they elicited marked hyperthermia. 80,81 Moreover, interspecies differences in TRPV1 functioning further complicated research. While one TRPV1 antagonist appeared to be safe in