RT Journal Article
SR Electronic
T1 Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1606
OP 1616
DO 10.1136/gut.2005.076778
VO 55
IS 11
A1 M R Ebrahimkhani
A1 S Kiani
A1 F Oakley
A1 T Kendall
A1 A Shariftabrizi
A1 S M Tavangar
A1 L Moezi
A1 S Payabvash
A1 A Karoon
A1 H Hoseininik
A1 D A Mann
A1 K P Moore
A1 A R Mani
A1 A R Dehpour
YR 2006
UL http://gut.bmj.com/content/55/11/1606.abstract
AB 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 α smooth muscle actin (α-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 δ 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 δ1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to δ1 and δ2 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.