Zsa Zsa Weerts

Chapter 4 96 regarding TRP channel involvement in visceral pain generation mostly focus on inflammation. Although animal colitis models have provided a wealth of information, alternative mechanisms of TRP channel sensitization should be explored. As discussed above, IBS is highly heterogeneous. Further insights in the mechanisms underlying IBS are needed in order to expand our knowledge of peripheral nociception and ultimately guide IBS treatment development. Conclusions In summary, TRPV1, TRPV4, TRPA1 and TRPM8 have been shown to play important roles in visceral pain generation and inhibition, making them potential targets in the treatment of IBS. TRPV1 antagonists have proven to be potent analgesics, but it remains difficult to produce compounds with an acceptable safety profile. Different strategies targeting TRPV1 ( i.e . modality-selective antagonism) or downstream molecules (NK1 or NK2 antagonists or somatostatin agonists) may solve this issue. TRPV1 desensitization strategies may provide suitable alternatives, yet short-term adverse effects may limit treatment adherence. In contrast, TRPV1 cross-desensitization with peppermint oil is attractive because of the low prevalence of adverse effects. The mechanism of action of peppermint oil however appears to reach beyond TRP channel signalling. In addition, TRPV4 and TRPA1 provide promising new targets. In our opinion, TRPA1 represents an important candidate for the development of new treatments of visceral pain. Its putative implication in mechanosensation in hyperalgesia but apparent lack of such function under basal conditions suggests a major role in IBS. Moreover, early TRPA1 antagonists have proven to be safe in clinical trials, rendering TRPA1 targeted therapy less of a pharmaceutical challenge than TRPV1 inhibition.