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TRP channels as therapeutic targets in IBS 83 4 TRPV1 functioning in (post-)inflammatory conditions As discussed above, the mediators of neurogenic inflammation are known to sensitize TRPV1. In addition, systemic inflammatory mediators have been shown to be involved in both sensitization and activation of TRPV1 (see Table 4.2 ). 30 Their potential relevance to IBS pathophysiology is evident, as many have postulated a role for subclinical inflammation in IBS. 5 However, inflammation has been argued to be within the physiological range in IBS. 6 Moreover, a study measuring poly-unsaturated fatty acids in colon biopsy material from IBS-D patients and healthy controls, failed to demonstrate differences in concentrations of lipoxygenase products (TRPV1 agonists). 31 It is possible that the role of inflammatory mediators in TRP channel sensitization is limited to post- inflammatory hyperalgesia, as encountered in post-infectious IBS and IBD in remission. Animal studies have provided evidence for TRPV1 mediated post-inflammatory hyperalgesia, using experimental colitis models induced by dextran sodium sulphate. After recovery from colitis, TRPV1 deficient mice showed no pain-related behavioural responses or increased visceromotor responses to colorectal distension, whereas these responses were readily observed in wildtype mice. 32 Another explanation for inflammation mediated hyperalgesia in IBS could be related to histamine. Barbara et al . observed increased numbers of mucosal mast cells in close proximity to sensory nerves in colon biopsies of IBS patients, 33 and these findings have been confirmed in a more recent study. 28 Moreover, Wouters et al . demonstrated an increased Ca 2+ response and increased number of responding neurons to capsaicin in histamine pre-treated biopsy specimens of healthy volunteers. 34 Immunostaining showed co-expression of histamine receptor H1 (HRH1) and TRPV1 on submucosal neurons in both IBS patients and healthy controls. A functional coupling of these receptors therefore appears likely. In a proof-of-concept trial, the same study group demonstrated a significant decrease in abdominal pain scores in IBS patients after 12 weeks of treatment with the HRH1 antagonist ebastine, as compared to placebo. Unfortunately, not all patients reported pain relief, emphasising the heterogeneity of the IBS patient population. Chronic stress and epigenetics IBS is often described to be a disorder of the brain-gut axis. In this model, psychological stress is generally accepted as a key factor influencing GI symptoms and vice versa. Importantly, animal models have suggested both glucocorticoid- and catecholamine- mediated TRPV1 upregulation. 35,36 In addition, epigenetic mechanisms may regulate the effects of chronic stress on TRPV1 expression. Increased histone acetylation of the