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Molecular basis of abdominal pain in IBD is not fully characterized. Serotonin (5-HT) increases visceral pain severity and contributes to exacerbation of inflammation. Moreover, it is well established that decreased anandamide (AEA) signaling in the gut increases visceral pain severity. The aim of this study was to investigate the interplay between 5-HT and endocannabinoid signaling in colitis.We used 3% DSS in drinking water to induce colitis in mice. From day 3 5-HT was administered for 5 days and each day visceromotor response to colorectal distention (CRD) was measured. Expression of cannabinoid (CB) receptors as well as enzymes responsible of biosynthesis and degradation of endocannabinoids were investigated. Moreover, endocannabinoid levels were assessed by mass spectrometry. Additionally, we measured the expression of enzymes synthesizing 5-HT and AEA in the colon of IBD patients and healthy controls.Chronic exposure to 5-HT increased visceromotor response to CRD and worsened colitis, which was associated with decrease of AEA via 5-HT3 and 5-HT4 receptors. Moreover, exposure to 5-HT led to the downregulation of CB1 receptors. Colonic levels of N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which is responsible for synthesis of AEA, significantly declined after chronic treatment with 5-HT and this effect was reversed by the 5-HT3 and 5-HT4 receptor antagonists. NAPE-PLD was also downregulated in the colon of UC patients.Our study shows a link between 5-HT and endocannabinoid signaling pathways in IBD. Thus, pharmacological blockade of 5-HT signaling or supplementation with endocannabinoids in the gut might be of benefit in severe cases of abdominal pain in IBD.