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µ-opioid receptor activation prevents acute hepatic inflammation and cell death.
  1. Dania Chakass (d-chakass{at}chru-lille.fr)
  1. Inserm U795, France
    1. David Philippe
    1. Inserm U795, France
      1. Edmone Erdual
      1. Inserm U795, France
        1. Sebastien Dharancy (s6{at}chru-lille.fr)
        1. Inserm U7905, France
          1. Mathilde Malapel
          1. Inserm U795, France
            1. Caroline Dubuquoy
            1. Inserm U795, France
              1. Xavier Thuru (xavthur{at}wanadoo.fr)
              1. Inserm U795, France
                1. Jerome Gay
                1. Inserm U795, France
                  1. Claire Gaveriaux-Ruff
                  1. UMR 7104 CNRS, Univ Louis-Pasteur Strasbourg 1, France
                    1. Pierre Dubus
                    1. EA 2406, Univ Bordeaux 2, France
                      1. Philippe Mathurin
                      1. Inserm U795, France
                        1. Brigitte L. Kieffer
                        1. UMR 7104 CNRS, Univ Louis-Pasteur Strasbourg 1, France
                          1. Pierre Desreumaux (pdesreumaux{at}chru-lille.fr)
                          1. Inserm U795, France
                            1. Mathias Chamaillard (card15{at}hotmail.fr)
                            1. Inserm U795, France

                              Abstract

                              Background & 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 hypothesized 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 biopsies specimens and peripheral blood mononuclear cells of untreated patients with chronic hepatitis C virus infection and controls, primary hepatocytes, cell lines was determined by quantitative PCR, immunoblotting and/or immunohistochemistry. The effects of peripheral MOR agonist (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 (CCl4)-induced hepatitis. The role of DAMGO in cell death was investigated by using TUNEL analysis and quantification of lactate dehydrogenase release.

                              Results: Herein, we report a key role of MOR in the prevention of acute hepatic inflammation and cell death in vivo and in vitro. Notably whereas MOR gene expression was increased transiently in model of acute liver injury and TNF-a-treated HepG2 cells, we found an impaired expression of MOR mRNA in human chronic hepatitis C samples. Furthermore, preventive administration of the selective MOR agonist DAMGO enhanced hepatoprotective-signaling pathways in vivo that were blocked by using naloxone methiodide. Consistently, genetic and pharmacological inhibition of MOR enhanced the severity associated to experimental hepatotoxin-induced hepatitis. Finally, we showed that treatment with DAMGO prevented cell death in vitro in HepG2 cells in a MOR-dependent manner and Concanavalin-A- and CCl4-induced cell death in vivo, providing a possible explanation for the anti-inflammatory role of MOR activation in the liver.

                              Conclusions: In conclusion, our results indicate that MOR agonists may prevent acute hepatitis and hold promising therapeutical use to maintain remission in both chronic inflammatory bowel and liver diseases.

                              • µ-opioid receptor
                              • cell death
                              • hepatic inflammation
                              • liver injury
                              • naloxone methiodide

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