LIVER

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats

M R Ebrahimkhani¹, S Kiani², F Oakley³, T Kendall³, A Shariftabrizi², S M Tavangar⁴, L Moezi², S Payabvash², A Karoon², H Hoseininik², D A Mann³, K P Moore⁵, A R Mani⁵, A R Dehpour²

¹ Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, and the UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, University College London, London, UK
² Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
³ Liver Group, Southampton General Hospital, University of Southampton, Southampton, UK
⁴ Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
⁵ The UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, University College London, London, UK

Correspondence to:
Professor K P Moore
The UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, University College London, Rowland Hill St, London NW3 2PF, UK; kmoore{at}medsch.ucl.ac.uk

Aim: The aim of this study was to investigate the hypothesis that the opioid system is involved in the development of hepatic fibrosis.

Methods: The effect of naltrexone (an opioid receptor antagonist) on hepatic fibrosis in bile duct ligated (BDL) or sham rats was assessed by histology and hepatic hydroxyproline levels. Liver matrix metalloproteinase 2 (MMP-2) was measured by zymography, and smooth muscle actin (-SMA) and CD45 (leucocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic glutathione (GSH)/oxidised glutathione (GSSG) and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterised by reverse transcriptase-polymerase chain reaction, and the effects of selective opioid receptor agonists on cellular proliferation, tissue inhibitor of metalloproteinase 1 (TIMP-1), and procollagen I expression in HSCs determined.

Results: Naltrexone markedly attenuated the development of hepatic fibrosis as well as MMP-2 activity (p<0.01), and decreased the number of activated HSCs in BDL rats (p<0.05). The development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S-nitrosothiols, which were partially or completely normalised by treatment with naltrexone, respectively. Activated rat HSCs exhibited expression of 1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to ₁ and ₂ agonists, respectively.

Conclusions: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.

Abbreviations: BDL, bile duct ligated; MMP, matrix metalloproteinase; -SMA, smooth muscle actin; GSH, glutathione; GSSG, oxidised glutathione; HSC, hepatic stellate cell; RT-PCR, reverse transcriptase-polymerase chain reaction; TIMP, tissue inhibitor of metalloproteinase; SDS, sodium dodecyl sulphate; NO, nitric oxide; ALP, alkaline phosphatase; ALT, alanine aminotransferase; PDGF, platelet derived growth factor; ct, cycle threshold; HCV, hepatitis C virus

Keywords: liver fibrosis; opioids; glutathione; tissue inhibitor of metalloproteinase; hepatic stellate cells; cirrhosis

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