Systemic Administration of Sialorphin Attenuates Experimental Colitis in Mice via Interaction With Mu and Kappa Opioid Receptors

Background and Aims: Pharmacological treatment and/or maintenance of remission in inflammatory bowel disease [IBD] is currently one of the biggest challenges in the field of gastroenterology. Here we aimed to assess the anti-inflammatory effect and the mechanism of action of sialorphin, the natural blocker of the endogenous opioid peptide-degrading enzymes neprilysin [NEP] and aminopeptidase N [APN], in mouse models of IBD and the changes in the expression of these enzymes in IBD patients. Methods: We used two models of experimental colitis in mice [2,4,6-trinitrobenzene sulphonic acid [TNBS]-and dextran sulphate sodium [DSS]-induced]. Macroscopic score, ulcer score, colonic wall thickness, and myeloperoxidase [MPO] activity were recorded. Additionally, we measured the expression of NEP and APN in the colon of IBD patients and healthy controls. Results: We showed that sialorphin attenuated acute, semichronic, and relapsing TNBS-induced colitis in mice after systemic administration, and its anti-inflammatory action is associated with mu and kappa opioid receptors. Conclusions: We show that indirect stimulation of opioid receptors by the blockade of NEP and APN is a promising pharmacological strategy for the treatment of IBD, and may become of greater importance than the use of classical opioid agonists.