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Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats
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Dr Mohammed Ebrahimkhani
Professor Fiona Oakley
Professor Derek Mann
Ebrahimkhani MR, Kiani S, Oakley F, Kendall T, Shariftabrizi A, Tavangar SM, Moezi L, Payabvash S, Karoon A, Hoseininik H, Mann DA, Moore KP, Mani AR, Dehpour AR
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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 alpha-actin (alpha-SMA) and CD45 (leukocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic GSH/GSSG and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterized by RT-PCR, and the effects of selective delta-opioid receptor agonists on cellular proliferation, TIMP-1 (tissue inhibitor of metalloproteinase-1) and pro-collagen 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 delta1 receptors, with increased pro-collagen I expression, and increased TIMP-1 expression in response to delta1 and delta2 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.
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