Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats.
OBJECTIVE
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 alpha smooth muscle actin (alpha-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 delta 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 delta1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to delta(1) and delta(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.
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.
M R
MR
Ebrahimkhani
S
S
Kiani
F
F
Oakley
T
T
Kendall
A
A
Shariftabrizi
S M
SM
Tavangar
L
L
Moezi
S
S
Payabvash
A
A
Karoon
H
H
Hoseininik
D A
DA
Mann
K P
KP
Moore
A R
AR
Mani
A R
AR
Dehpour
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D024042:Collagen Type I; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D019715:Tissue Inhibitor of Metalloproteinase-1; D009569:Nitric Oxide; D009271:Naltrexone; D020778:Matrix Metalloproteinase 2