IBD represents a relevant inflammatory disorder of the gastrointestinal tract that requires an interdisciplinary collaboration of gastroenterologists and visceral surgeons to provide precise and individualized treatment options. Especially adequate management of chronic symptoms and an effective therapy of complications are crucial, but also highly challenging in the overall treatment plan of these patients. Therefore, the present study focused on abdominal pain typically resulting from intestinal inflammation and displaying one of the leading symptoms in IBD and on the other hand on malignant transformation, especially the occurrence of CRC as one of the most incisive complications in this inflammatory disorder. In the first part of the present work, we therefore started to investigate nociceptive signaling which comprises a complex network of diverse areas, neurons and interacting neurotransmitter systems with special regard to the GABAergic and the opioidergic system. We initially examined the role of GABAergic neurotransmission with respect to GABABR-mediated effects in multiple in vitro experiments which should serve as a basis for future in-depth studies. However, besides GABAergic transmission, administration of opioids and subsequent activation of the opioidergic system still represents the mainstay in clinical practice to inhibit nociceptive signaling thus providing adequate pain relief in many inflammatory disorders, especially in IBD. Nevertheless, the powerful analgesic actions of opioids are counteracted by their severe side effects which markedly limit their prevalent use hence indicating the need for new potent analgesic drugs with low side effect profiles. NFEPP, a fentanyl analogue, typifies such a novel compound which was designed to activate MORs only in acidic microenvironments thereby providing potent analgesia without opioid-typical side effects (Spahn et al., 2017). We next examined the actions of the potential alternative NEPP in a murine model of colonic inflammation employing multiple in vivo and in vitro experiments combined with a translational approach in human colonic tissue. Interestingly, we found that during a colonic inflammation which closely mimics the inflammatory state of ulcerative colitis, repeated treatment with NFEPP effectively inhibited visceral nociception without inducing opioid-typical adverse events and its actions were strictly confined to acidic areas which corresponded to sites of histologically verified inflammation within the inflamed colonic wall. Moreover, in our murine model of IBD, we additionally revealed that NFEPP maintained its antinociceptive actions over time and did not induce analgesic tolerance compared to fentanyl when applied at the same dose and dosing intervals. Finally, we substantiated our results by proving that NFEPP was also able to inhibit human colonic nociceptors under acidic conditions likely indicating its potential future transition into clinical practice as a novel safe and effective analgesic drug for adequate pain control in inflammatory gastrointestinal disorders such as IBD. In the second part, we then investigated sporadic and IBD-related CRC. Identification of distinctive tumor characteristics will likely codetermine therapeutical procedures and survival predictions. In this context, primary tumor sidedness is assumed to be of predictive value based on diverse clinicopathological characteristics found in right- and left-sided tumor localizations. Thus, we first examined an unselected population of patients with sporadic CC stage I-IV at our institution and did not reveal an association of primary tumor sidedness with survival outcomes in our cohort although demonstrating diverse clinicopathological characteristics in the right- and left-sided group. We next conducted a multicentric study of IBD-related non-metastatic CRC and similarly disclosed that primary tumor sidedness did not affect overall and recurrence-free survival, but also found that clinicopathological features were equally distributed among a right- and left-sided tumor localization in these patients likely referring to a unique nature of IBD-related CRC. Interestingly, CEA levels and parameters that were related to lymph node status significantly impacted the overall outcome in sporadic and IBD-related CRC highlighting the relevance of common tumor load and affection of lymph nodes for patient mortality. Nevertheless, our results point out the imperative of future high-power and in-depth studies to clarify the question if primary tumor sidedness could ultimately dictate diverse therapeutical approaches in patients with sporadic and IBD-related CRC.
