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

Mohammad Ebrahimkhani, Samira Kiani, F. Oakley, T. Kendall, A. Shariftabrizi, S. M. Tavangar, L. Moezi, S. Payabvash, A. Karoon, H. Hoseininik, D. A. Mann, K. P. Moore, A. R. Mani, A. R. Dehpour

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Abstract

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 a 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.

Original languageEnglish (US)
Pages (from-to)1606-1616
Number of pages11
JournalGut
Volume55
Issue number11
DOIs
StatePublished - Nov 2006
Externally publishedYes

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Naltrexone
Narcotic Antagonists
Bile Ducts
Liver Cirrhosis
Liver
Hepatic Stellate Cells
Fibrosis
S-Nitrosothiols
Oxidation-Reduction
Procollagen
Tissue Inhibitor of Metalloproteinase-1
Glutathione Disulfide
Matrix Metalloproteinase 2
Opioid Receptors
Opioid Analgesics
CD45 Antigens
Biliary Liver Cirrhosis
Hydroxyproline
Reverse Transcriptase Polymerase Chain Reaction
Glutathione

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Ebrahimkhani, M., Kiani, S., Oakley, F., Kendall, T., Shariftabrizi, A., Tavangar, S. M., ... Dehpour, A. R. (2006). Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats. Gut, 55(11), 1606-1616. https://doi.org/10.1136/gut.2005.076778

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats. / Ebrahimkhani, Mohammad; Kiani, Samira; Oakley, F.; Kendall, T.; Shariftabrizi, A.; Tavangar, S. M.; Moezi, L.; Payabvash, S.; Karoon, A.; Hoseininik, H.; Mann, D. A.; Moore, K. P.; Mani, A. R.; Dehpour, A. R.

In: Gut, Vol. 55, No. 11, 11.2006, p. 1606-1616.

Research output: Contribution to journalArticle

Ebrahimkhani, M, 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 2006, 'Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats', Gut, vol. 55, no. 11, pp. 1606-1616. https://doi.org/10.1136/gut.2005.076778
Ebrahimkhani, Mohammad ; Kiani, Samira ; Oakley, F. ; Kendall, T. ; Shariftabrizi, A. ; Tavangar, S. M. ; Moezi, L. ; Payabvash, S. ; Karoon, A. ; Hoseininik, H. ; Mann, D. A. ; Moore, K. P. ; Mani, A. R. ; Dehpour, A. R. / Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats. In: Gut. 2006 ; Vol. 55, No. 11. pp. 1606-1616.
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abstract = "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 a 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.",
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T1 - Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats

AU - Ebrahimkhani, Mohammad

AU - Kiani, Samira

AU - Oakley, F.

AU - Kendall, T.

AU - Shariftabrizi, A.

AU - Tavangar, S. M.

AU - Moezi, L.

AU - Payabvash, S.

AU - Karoon, A.

AU - Hoseininik, H.

AU - Mann, D. A.

AU - Moore, K. P.

AU - Mani, A. R.

AU - Dehpour, A. R.

PY - 2006/11

Y1 - 2006/11

N2 - 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 a 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.

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 a 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.

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