Background and aims: Recent studies with m opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. Patients and methods: Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8 + T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kB (NFkB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. Results: MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8 + T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor a mRNA expression in the colon of active IBD patients. Conclusions: Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.

Background and aims: The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the m-opioid receptor (MOR) agonists at the intestinal barrier, we hypothesised that MOR activation might also dampen acute hepatic inflammation and cell death-major determinants in the pathogenesis of liver diseases. Patients and methods: The expression of MOR in liver biopsy specimens and peripheral blood mononuclear cells of untreated patients with chronic hepatitis C virus infection and controls, primary hepatocytes and cell lines was determined by quantitative PCR, immunoblotting and/or immunohistochemistry. The effects of peripheral MOR agonist (D-Ala2,NMe-Phe4,Gly5-ol (DAMGO)) and/or antagonist (naloxone methiodide) were explored in two models of acute hepatitis in mice. MOR-deficient mice were used to evaluate the essential regulatory role of MOR during carbon tetrachloride (CCl 4 )-induced hepatitis. The role of DAMGO in cell death was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) analysis and quantification of lactate dehydrogenase release. Results: The key role of MOR in the prevention of acute hepatic inflammation and cell death in vivo and in vitro is reported. Whereas MOR gene expression increased transiently in the model of acute liver injury and TNFa-treated HepG2 cells, an impaired expression of MOR mRNA in human chronic hepatitis C samples was found. Furthermore, preventive administration of the selective MOR agonist DAMGO enhanced hepatoprotective-signalling pathways in vivo that were blocked by using naloxone methiodide. Consistently, genetic and pharmacological inhibition of MOR enhanced the severity associated with experimental hepatotoxin-induced hepatitis. Finally, treatment with DAMGO was shown to prevent cell death in vitro in HepG2 cells in a MOR-dependent manner and to prevent concanavalin A-and CCl 4 -induced cell death in vivo, providing a possible explanation for the anti-inflammatory role of MOR activation in the liver. Conclusions:The results indicate that MOR agonists may prevent acute hepatitis and hold promising therapeutic use to maintain remission in both chronic inflammatory bowel and liver diseases.

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