Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress.

Abstract

AIMS/BACKGROUND:

There are increasing number of evidences indicating the contribution of endogenous opioids in the pathophysiology of cholestatic liver disease. The aim of the present study was to determine the role of the endogenous-opioid system in the modulation of hepatocytes apoptosis and liver oxidant/anti-oxidant balance during chronic cholestasis in rats.

METHODS:

We induced cholestasis in rats by bile duct ligation (BDL). Naltrexone, an opioid antagonist, was administered at different doses (2.5, 5, 10, 20 and 40 mg/kg/day) to cholestatic animals for 5 weeks.

RESULTS:

Naltrexone prevented the cholestasis-induced decrease of hepatic glutathione levels at higher doses (20 and 40 mg/kg/day). In the next phase of the study, we evaluated the effects of 20 mg/kg/day naltrexone treatment on hepatic damage indices and liver oxidant/anti-oxidant balance in 5-week BDL rats. There was a marked increase in the number of apoptotic hepatocytes as well as serum liver enzymes and hepatic lipid peroxidation levels in cholestatic rats compared with sham-operated animals 5 weeks after the operation. Liver anti-oxidant enzyme activities were significantly reduced in cholestatic rats compared with controls. Chronic treatment with naltrexone significantly improved all the aforementioned indices in comparison with saline-treated cholestatic rats.

CONCLUSION:

Our findings demonstrate that the administration of opioid antagonist is protective against hepatic damage in a rat model of chronic cholestasis. We suggest that increased levels of endogenous opioids contribute to hepatocytes apoptosis in cholestasis, possibly through downregulation of liver anti-oxidant defense.

• Authors: Seyedmehdi Payabvash, Saman Kiumehr, Behtash Ghazi Nezami, Ali Zandieh, Pasha Anvari, Seyed Mohammad Tavangar, Ahmad Reza Dehpour
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 27 Issue 4 Pg. 538-47 (May 2007) ISSN: 1478-3223 [Print] United States
• PMID: 17403194 (Publication Type: Journal Article)

Chemical References

• Analgesics, Opioid
• Biological Factors
• Narcotic Antagonists
• Naltrexone

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Apoptosis (drug effects)
• Biological Factors (physiology)
• Cholestasis (drug therapy, pathology)
• Chronic Disease
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hepatocytes (cytology, drug effects)
• Liver (metabolism)
• Naltrexone (administration & dosage, pharmacology, therapeutic use)
• Narcotic Antagonists (pharmacology)
• Oxidative Stress (drug effects, physiology)
• Rats