Opioid receptor blockade reduces Fas-induced hepatitis in mice

Abstract

Fas (CD95)-induced hepatocyte apoptosis and cytotoxic activity of neutrophils infiltrating the injured liver are two major events leading to hepatitis. Because it has been reported that opioids, via a direct interaction, sensitize splenocytes to Fas-mediated apoptosis by upregulating Fas messenger RNA (mRNA) and modulated neutrophil activity, we assumed that opioids may participate in the pathophysiology of hepatitis. Using the hepatitis model induced by agonistic anti-Fas antibody in mice, we showed that opioid receptor blockade reduced liver damage and consequently increased the survival rate of animals when the antagonist naltrexone was injected simultaneously or prior to antibody administration. Treatment of mice with morphine enhanced mortality. Naloxone methiodide-a selective peripheral opioid antagonist-had a protective effect, but the absence of opioid receptors in the liver, together with lack of morphine effect in Fas-induced apoptosis of primary cultured hepatocytes, ruled out a direct effect of opioids on hepatocytes. In addition, the neutralization of opioid activity by naltrexone did not modify Fas mRNA expression in the liver as assessed with real-time quantitative polymerase chain reaction. Injured livers were infiltrated by neutrophils, but granulocyte-depleted mice were not protected against the enhancing apoptotic effect of morphine. In conclusion, opioid receptor blockade improves the resistance of mice to Fas-induced hepatitis via a peripheral mechanism that does not involve a down-modulation of Fas mRNA in hepatocytes nor a decrease in proinflammatory activity of neutrophils.

Opioid receptor-independent protection of ischemic rat hepatocytes by morphine

“…Unlike cardiomyocytes, hepatocellular protection by morphine was not associated with opioid receptors. Recent report showed that the liver is lack of opioid receptors [21], which is consistent with our results. The absence of opioid receptors in the liver may also explain why the dose of morphine for hepatocellular protection (50 μM) was higher than that required for protecting cardiomyocytes (1 μM) in which delta-and kappa-opioid receptors play a major role [22].…”

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

“…A brain site of opioid action is suspected (24,39,40). As an alternative, a direct peripheral action might be considered, although the presence of the MOR in liver and skeletal muscle remains poorly documented (41)(42)(43)(44).…”

Naltrexone Protects Against Lipopolysaccharide/D-Galactosamine–Induced Hepatitis in Mice

“…Recently, Jaume and his colleagues reported that naltrexone reduces Fas-induced hepatitis in mice (48) and that opioid receptor antagonist improves the resistance of mice to Fas-induced hepatitis via a peripheral mechanism that does not involve a downmodulation of Fas mRNA in hepatocytes nor a decrease in pro-inflammatory activity of neutrophils. As mentioned in the previous discussions that liver damage has been associated with overproduction of ROS (1 -6) or TNF-α (15 -17, 34 -42), these publications lend support to our current results and our earlier report indicated that naltrexone is capable of preventing and / or protecting against LPS or LPS / D-gal-induced liver damage via modulation of ROS or TNF-α (18).…”