title: micro-Opioid receptor activation prevents acute hepatic inflammation and cell death.
abstract: OBJECTIVE
  The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the mu-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.
  
  
  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 TNFalpha-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U795, University of Lille 2, Digestive Tract Diseases and Nutrition Department, 59037, Lille Cedex, France.
authors.forename: Dania
authors.initials: D
authors.lastname: Chakass
authors.forename: David
authors.initials: D
authors.lastname: Philippe
authors.forename: Edmone
authors.initials: E
authors.lastname: Erdual
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dharancy
authors.forename: Mathilde
authors.initials: M
authors.lastname: Malapel
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubuquoy
authors.forename: Xavier
authors.initials: X
authors.lastname: Thuru
authors.forename: Jerome
authors.initials: J
authors.lastname: Gay
authors.forename: Claire
authors.initials: C
authors.lastname: Gaveriaux-Ruff
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
mesh_terms: D000208:Acute Disease; D000818:Animals; D001706:Biopsy; D002251:Carbon Tetrachloride; D016923:Cell Death; D003208:Concanavalin A; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000627:therapeutic use; D015870:Gene Expression; D006505:Hepatitis / Q000378:metabolism / Q000517:prevention & control*; D019698:Hepatitis C, Chronic / Q000378:metabolism; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D014409:Tumor Necrosis Factor-alpha; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D003208:Concanavalin A; D002251:Carbon Tetrachloride