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Chapter 4 92 *Effects mediated by TRPM8 activation 61 Desensitization The desensitizing properties of TRPV1 agonists such as capsaicin have been exploited for many years by topical preparations in the treatment of neuropathic pain. 86 At this moment, only one small randomized crossover study investigated the effects of six weeks of chilli treatment in IBS-D patients. 87 At the end of treatment, patients reported significantly decreased post-prandial abdominal burning sensations. Similar positive effects have been demonstrated in epigastric pain in patients with functional dyspepsia. 88 An important drawback of capsaicin therapy however, is its short-term aggravating effects, possibly limiting adherence in the clinical setting. Therefore, more studies are needed to evaluate efficacy and feasibility in a larger IBS population. In addition, it remains to be established at which dose, frequency and length of administration repeated capsaicin is able to, if all, induce desensitization of TRPV1- positive nerve endings in the gut. Ultra-rapid desensitization using potent agonists offer a theoretical background for achieving a fast analgesic response. One of these ultra-potent TRPV1 agonists is resiniferatoxin, which causes sustained calcium influx, resulting in a cytotoxic intracellular free calcium concentration and consequent axonal damage of TRPV1-positive neurons. 89 Unfortunately, its potency also poses challenges. Similar to first generation TRPV1 antagonists, resiniferatoxin increases the heat pain threshold. Moreover, high or repeated systemic doses of resiniferatoxin induce long-lasting damage to TRPV1-positive neurons, 90 rendering it not suitable for therapeutic applications in IBS. Cross-desensitization Another mechanism aimed at analgesia is related to TRPV1 channel cross- desensitization. As mentioned above, TRPM8 activation is thought to provide antinociceptive effects through subsequent inhibition of TRPV1 and TRPA1. Peppermint oil, containing the TRPM8 agonist menthol, exploits these beneficial effects and is registered for the use in IBS in several countries. 91 It should be noted that the exact mechanism of action remains to be elucidated. Moreover, its effects appear to reach beyond TRP channel signalling as calcium channel mediated smooth muscle relaxation has been observed in vitro in human colon tissue without the involvement of TRPM8. 92