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Chapter 4 88 TRPM8 Transient Receptor Potential Melastatin 8 (TRPM8) appears to be one of the least studied TRP channels in humans. Only very recently TRPM8 polymorphisms have been demonstrated to be associated with slower colonic transit and an increased risk of IBS- C and IBS-M in humans. 58 However, data on TRPM8 functioning is mainly based on animal studies, limiting our understanding of its role in visceral pain generation. Our current knowledge of TRPM8 is that it has a role in thermosensation (primarily low temperatures). 59 Several chemical compounds are able to activate TRPM8, among others menthol and icilin. Many will acknowledge that the sensation of mentholated liniments is difficult to describe. Cold and burning perceptions alternate upon application. Because of these opposing sensory inputs, menthol is thought to also activate channels other than TRPM8. Indeed, some authors have pointed to menthol- induced TRPA1 activation in order to explain the diverse psychophysical sensations after topical application of menthol. 60 Moreover, coupling of TRPM8 to both TRPV1 and TRPA1 has been demonstrated previously. 61 As mentioned above, AITC is able to cause mechanical hypersensitivity through TRPA1 activation. This effect, however, does not occur after pre-treatment with icilin. In contrast, icilin-induced mechanical desensitization is absent in TRPA1 deficient mice, indicating that the effect was TRPA1 mediated. Likewise, capsaicin is able to cause mechanical desensitization, but not after icilin pre-treatment. 61 TRPM8 is therefore thought to inhibit chemo- and mechanosensory responses of TRPA1 and TRPV1, and thus provide antinociceptive effects through cross-desensitization. In addition, visceral TRPM8 is thought to have a role in inflammation. Human studies have revealed increased TRPM8 expression in colonic biopsy material from IBD patients as compared to healthy controls. 62 Several experimental colitis models in mice have suggested protective effects of TRPM8 activation. In these studies, icilin treatment significantly attenuated induced colitis in wildtype mice, but not in TRPM8 deficient ones. 62-64 The protective effects of TRPM8 activation have been linked to CGRP, which co-localizes with TRPM8 in the human colon. 64 Although the pro-inflammatory effects of CGRP in neurogenic inflammation are evident, primarily consisting of vasodilation, anti- inflammatory effects of the neuropeptide have been observed as well. 65,66 De Jong et al . demonstrated expression of the components of the CGRP receptor, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein-1 (RAMP1), on CD11c+ dendritic cells in the murine spleen. 64 CGRP knockout mice were shown to have higher levels of pro-inflammatory cytokines (including TNF- and IL-6) in chemically induced acute colitis, as compared to wildtype mice. Moreover, CD11c+ dendritic cells