Zsa Zsa Weerts

Chapter 4 84 TRPV1 promoter has been demonstrated in chronic stress models in rats, resulting in TRPV1 upregulation in DRG derived neurons. 37 Furthermore, the epigenetics of visceral pain perception have been investigated in diarrhoea predominant IBS patients. 27 Two miRNAs known to decrease TRPV1 expression, miR-199a and miR-199b, were found to be significantly downregulated and shown to correlate with pain scores. Taken together, these results indicate epigenetic alterations, possibly under the influence of psychological stress, modulate TRPV1 functioning in IBS. Activation of sensitized nociceptors Currently identified endogenous agonists of TRPV1, as well as the other TRP channels discussed in this review, are primarily related to inflammation (see Table 4.2 ). As already noted, (subclinical) inflammation is not the sole underlying mechanism in IBS. Furthermore, it is unknown whether the concentrations of endocannabinoids known to activate TRPV1 in vitro are high enough in vivo in order to achieve activation. 38 This constitutes a significant gap in our knowledge of peripheral nociception in IBS, as it remains unclear what stimuli ultimately activate sensitized nociceptors in vivo. Although capsaicin is a common dietary constituent, it is unlikely to be a major factor in abdominal pain generation in IBS. Current understanding of intestinal signalling suggests that nociceptive signals are generated by exciting sensitized nociceptors as a result of mechanical stimulation or distension. These mechanical stimuli could be related to physiological motor responses of the intestine. 6 High amplitude colonic contractions have been shown to be of a magnitude above nociceptive thresholds in visceral hypersensitivity. Therefore, mechanical stimuli generated by the gut itself may be responsible for the generation of pain symptoms through sensitized nociceptors. TRPV4 Studies investigating expression patterns of Transient Receptor Potential Vanilloid 4 (TRPV4) in the human colon have demonstrated immunoreactivity in the submucosa and serosa. 39 Initially termed vanilloid receptor-related osmotically activated channel (VR-OAC), this channel has been implicated in the detection of osmolarity changes. 40 In addition, TRPV4 is now known to sense strong acidosis, temperatures >24°C and, among others, the synthetic phorbol ester alpha-phorbol 12,13-didecanoate (4 PDD) (see Table 4.2 ). Currently identified endogenous agonists include anandamide and the poly-unsaturated fatty acid metabolites 5,6-epoxyeicosatrienoic acid (5,6-EET) and 8,9- EET.