Mechanisms of Abdominal Pain in Paediatric Inflammatory Bowel Disease

PhDIntroduction. Inflammatory bowel disease (IBD) is a condition affecting more than 3 million people in Europe and the USA combined. Patients report pain as one of the most severe and debilitating symptoms leading to a lower quality of life. Current analgesics lack efficacy for the treatment of visceral pain or produce unacceptable side effect profiles. New targets are needed. Aims and methods. The aim of this thesis was to examine the activation of primary visceral afferents in C57BL/6 mice in response to biopsy supernatants from paediatric patients with IBD (Crohn’s disease and ulcerative colitis) and functional abdominal pain syndrome (FAPS). By comparing the expression of pro-inflammatory and pro-nociceptive mediators in these biopsy samples with patient pain scores and afferent nerve recording activation, we identified putative mediators likely to be responsible for causing pain. The ability of inflammatory mediators to drive visceral nociception was then examined by their exogenous application in recordings of mouse and human visceral nociceptor activity. Results. Nerve activation increased significantly in response to biopsy supernatants from FAPS, CD, and UC patients, when compared to controls. Supernatant IL-8, TNFα, IL-6 and IL-1β, levels were increased in IBD samples compared with control patients. Analysis of mRNA expression also showed high levels of pro-inflammatory cytokines and raised MMP-1, MMP-3, MMP-9, MMP-12, and MMP-19 in IBD samples. The expression of MMP-12 in biopsy samples from Crohn’s patients significantly correlated with afferent firing suggesting a causative role. This was confirmed by exogenously application of MMP-12 stimulated afferent firing and sensitised responses to mechanical stimulation and inflammatory mediators. UC samples showed TIMP-1 as an effective inhibitor of afferent firing. Conclusion. Data from this study demonstrates that the bowel of patients with IBD and FAP releases pro-nociceptive mediators which stimulate visceral afferents. MMP’s play an important role in the afferent activation mediated by IBD samples suggesting that exploiting the endogenous inhibitor TIMP-1 could be a key target for future therapeutic strategies