Zsa Zsa Weerts

Chapter 4 94 One additional mediator of neurogenic inflammation has been implicated as a potential target in the development of analgesic therapies. Somatostatin, originating from capsaicin-sensitive sensory afferents, counteracts pro-inflammatory neuropeptides CGRP and substance P. Indeed, the potent analgesic effects of somatostatin have long been recognized. 98 Early studies using the somatostatin analogue octreotide have demonstrated increased thresholds of visceral sensory perception in IBS patients. 99,100 Moreover, anti-hyperalgesic effects of selective agonists of somatostatin receptor 1 and 2 have been reported in induced visceral hypersensitivity in mice. 101 Therefore, somatostatin analogues or receptor agonists may provide additional therapeutic strategies in visceral pain. Clinical studies will need to substantiate their applicability in IBS patients. RNA-based therapy The observation of decreased expression of several TRPV1 targeting miRNAs in IBS patients suggests an opportunity for RNA-based therapy. The therapeutic potential of post-transcriptional gene silencing by RNA interference is increasingly being recognized. 102 The major benefit of synthetic siRNAs is their high target specificity, preventing the suppression of unrelated genes. Unfortunately, several challenges have yet to be overcome before RNA-based therapy can become a therapeutic option in IBS. The oral bioavailability of oligonucleotides is limited, confining the possible modes of administration to more invasive approaches. Furthermore, the effects are only transient, demanding repeated treatment. Therefore, there is a need for stable TRPV1 targeting siRNAs that are readily absorbed in the GI tract. Exploiting new targets Our current knowledge on the role of visceral TRPV4 and TRPA1 in humans is limited. Nonetheless, data from animal studies, discussed above, suggest that these channels are viable targets for IBS therapy. The previous discovery of elevated levels of the endogenous TRPV4 agonist 5,6-EET in IBS-D patients and the putative implication of TRPV4 in mechanical hypersensitivity justify the need for further research. TRPA1- targeted therapy has been explored in animal models of visceral pain. However, contrasting evidence was found demonstrating attenuated visceral nociception in rodents with both TRPA1 antagonists as agonists. 54,103,104 It is unclear whether the mechanism of action of the latter was based on desensitization. Arguing against such a mechanism is the observation that reduced abdominal contractions were observed in mice after a single oral dose of a TRPA1 agonist. Furthermore, one TRPA1 antagonist has recently shown efficacy in patients with painful diabetic neuropathy, and several