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TRP channels as therapeutic targets in IBS 89 4 were found to be co-localized with CGRP positive fibres in the murine colon. CGRP was therefore thought to exert a protective role in colitis via inhibition of the release of pro-inflammatory cytokines, through interaction with local dendritic cells. Indeed, TRPM8 deficient mice showed significant improvement in disease activity after treatment with recombinant CGRP, whereas no effect of treatment was observed in wildtype mice with induced colitis. Paradoxically, enhanced CGRP expression levels have been observed in mucosal fibres of TRPM8 deficient mice. 62 This discrepancy has yet to be clarified, although it is likely that a disrupted colonic CGRP release prevents the neuropeptide from reaching its effector. Taken together, these results suggest that TRPM8 upregulation is a protective mechanism aimed at mitigating tissue inflammation. Therefore, TRPM8 could theoretically protect against nociceptor sensitization by inflammatory mediators. Non-neuronal TRP channel expression As already mentioned, TRP channels are expressed by a multitude of cell types including those of non-neuronal origin (both intestinal and extra-intestinal). 67 Examples of non- neuronal cells expressing TRP channels include vascular smooth muscle cells, endothelial cells, keratinocytes and intestinal epithelial cells. The possible involvement of the latter in IBS pathophysiology should not be overlooked. Increased intestinal permeability has been demonstrated in IBS-D patients, 68 and has been associated with visceral hypersensitivity. 69 In two studies, TRPV4 activation with 5,6-EET and 4 PDD resulted in increased intestinal permeability. 70,71 One of the proposed mechanisms was via downregulation of tight junction proteins. However, conflicting results have been obtained for the role of TRPV1 in regulating intestinal permeability. Capsaicin has previously been shown to increase permeability. In contrast, the endocannabinoid-like compound oleoylethanolamine has been shown to be able to both increase and decrease intestinal permeability via TRPV1. 72 Similarly, the role of TRPA1 in the regulation of intestinal permeability remains controversial. Fothergil et al . demonstrated decreased trans-mucosal resistance in colon tissue from mice after AITC and cinnamaldehyde administration. 73 We demonstrated no effects on small intestinal permeability with the administration of cinnamaldehyde in twelve healthy controls. 74 It therefore remains unclear to what extent TRP channels contribute to IBS pathophysiology via altering intestinal permeability. Motility effects of TRP channel activation Although we here focus on the role in visceral nociception, it should be noted that TRP channels are known to affect gut motor function as well. 21 The effects of TRP channel