Sa2019 Regulation of Inflammation-Associated Abdominal Pain by Colitogenic Mucosal CD4+ T Lymphocytes: The Role of Opioids

Abstract

Inflammatory bowel diseases (IBD) are characterized by an uncontrolled inflammatory response to colonic luminal content involving both innate and adaptive immunity. Indeed, aberrant responses of CD4+ Th1 and Th17 lymphocytes against microbiota highly contribute to the development of IBD. We have previously shown that effector CD4+ T lymphocytes generated in response to microbes are responsible for inflammatory pain relief that occurs spontaneously within the few days following the initiation of the immune response. The endogenous T cell-dependent regulation of inflammatory pain is mediated by the local release of opioids that have been synthesized upon the activation of CD4+ T lymphocytes within draining lymph nodes (Boue J, et al. J. Immunol., 2011, 186:5078-5084). Given that the production of opioids is not restricted to a particular phenotype of effector CD4+ T lymphocytes (Boue J, et al. Pain, 2012, 153, 485-493), we wondered whether colitogenic CD4+ Th17 and Th1 lymphocytes that accumulate within inflamed colon also produce opioids and contribute to reduce inflammation-induced visceral pain. For this purpose, we used the colitis model induced by the transfer of Naive CD4+CD45RBhigh T lymphocytes into immune-deficient SCID mice. In this model, in which the absence of efficient regulation of the T cell response against microbiota leads to chronic inflammation of the gut, we showed that Th1 and Th17 lymphocytes isolated from inflamed colon 6 weeks after T cell transfer, expressed high level of endogenous opioids. The production of opioids by colitogenic CD4+ T lymphocytes was responsible for a significant reduction of inflammation-associated abdominal pain as assessed by colorectal distension. Indeed, visceral sensitivity was increased in mice locally treated with an opioid receptor antagonist, unable to cross the blood-brain barrier. Taken together, our results indicate that colitogenic mucosal CD4+ T lymphocytes that play a pivotal role in colitis pathogenesis reduce pain associated with inflammationinduced tissue injury.