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Chapter 4 80 counteracted by the anti-inflammatory effects of somatostatin, which has also been shown to be released by capsaicin-sensitive afferents. 23 Sustained disruptions in the balance of these pro- and anti-inflammatory neuropeptides may result in the pathological sensitization of nociceptive afferents, as well as local tissue inflammation (see Figure 4.1 ). Importantly, these processes do not seem to be limited to TRPV1, but also apply to the other TRP channels discussed in this review. Sensitization of TRPV1-expressing afferents has been demonstrated in IBS patients by increased perceptive responses to capsaicin in multiple studies. 20,24,25 Gonlachanvit et al . demonstrated that diarrhoea predominant IBS (IBS-D) patients experience greater abdominal burning after a single ingestion of a spicy meal or standard meal in combination with a capsaicin capsule, compared to healthy controls. 24 As symptoms developed within one hour after ingestion, proximal gut hypersensitivity to capsaicin was suggested to exist in these patients. Schmulson et al . showed a significantly decreased rectal pain threshold in IBS patients after a 7-day chilli rich diet compared to a diet without chilli, suggesting TRPV1-induced visceral hyperalgesia. 25 More recently, van Wanrooij et al . studied the effects of rectal capsaicin application in IBS patients. 20 Patients reported increased pain intensity, a similar effect lacking in healthy volunteers. Furthermore, the pain response appeared to be independent of anticipatory anxiety, suggesting a direct capsaicin effect on nociceptive mucosal afferents. Mechanisms underlying the increased capsaicin sensitivity in IBS patients have been studied extensively. Akbar et al . demonstrated upregulation in sigmoid mucosal samples of IBS patients. 19 This increase correlated with symptom severity, suggesting that an increase in afferent discharge through TRPV1 activation might be directly related to pain symptom generation. Our earlier study corroborated these findings, demonstrating increased transcription of TRPV1 in IBS patients, which also strongly correlated with symptom severity. 26 More recently, two studies confirmed the augmented expression of TRPV1 in colonic biopsies of IBS-D patients. 27,28 It should be noted that the overall density of innervation has been shown to be increased in IBS patients. Increased TRPV1 sensitivity may therefore be due to axonal sprouting rather than isolated TRPV1 upregulation, possibly as a result of increased nerve growth factor expression. 28,29 On the other hand, Van Wanrooij et al . were unable to objectify increased numbers of mucosal TRPV1 in colonic biopsies of IBS patients, as compared to healthy controls. 20 Even when the IBS patient group with visceral hypersensitivity (defined by decreased discomfort threshold during rectal distension) was analysed separately, no significant