Sensitization of colonic nociceptors by TNF alpha is dependent on TNFR1 expression and p38 MAPK activity

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut-related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception n disease states is required to facilitate this. The pro-inflammatory crokine TNF alpha is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNF alpha-triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. therefore hypothesized that TNFR1-evoked p38 MAPK activity may also be responsible for TNF alpha sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNF alpha-mediated increases in intracellular [Ca2+] and sensitization of capsaicin responses. The sensitizing effects of TNFa were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex viva colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNF alpha pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNF alpha-induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease.