-Opioid receptor activation prevents acute hepatic inflammation and cell death

Abstract

Background and aims: The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the m-opioid receptor (MOR) agonists at the intestinal barrier, we hypothesised that MOR activation might also dampen acute hepatic inflammation and cell death-major determinants in the pathogenesis of liver diseases. Patients and methods: The expression of MOR in liver biopsy specimens and peripheral blood mononuclear cells of untreated patients with chronic hepatitis C virus infection and controls, primary hepatocytes and cell lines was determined by quantitative PCR, immunoblotting and/or immunohistochemistry. The effects of peripheral MOR agonist (D-Ala2,NMe-Phe4,Gly5-ol (DAMGO)) and/or antagonist (naloxone methiodide) were explored in two models of acute hepatitis in mice. MOR-deficient mice were used to evaluate the essential regulatory role of MOR during carbon tetrachloride (CCl 4 )-induced hepatitis. The role of DAMGO in cell death was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) analysis and quantification of lactate dehydrogenase release. Results: The key role of MOR in the prevention of acute hepatic inflammation and cell death in vivo and in vitro is reported. Whereas MOR gene expression increased transiently in the model of acute liver injury and TNFa-treated HepG2 cells, an impaired expression of MOR mRNA in human chronic hepatitis C samples was found. Furthermore, preventive administration of the selective MOR agonist DAMGO enhanced hepatoprotective-signalling pathways in vivo that were blocked by using naloxone methiodide. Consistently, genetic and pharmacological inhibition of MOR enhanced the severity associated with experimental hepatotoxin-induced hepatitis. Finally, treatment with DAMGO was shown to prevent cell death in vitro in HepG2 cells in a MOR-dependent manner and to prevent concanavalin A-and CCl 4 -induced cell death in vivo, providing a possible explanation for the anti-inflammatory role of MOR activation in the liver. Conclusions:The results indicate that MOR agonists may prevent acute hepatitis and hold promising therapeutic use to maintain remission in both chronic inflammatory bowel and liver diseases.

Activation of μ opioid receptors modulates inflammation in acute experimental colitis

“…This concept is further supported by the suppression of the inhibitory effect of DAMGO on MPO and NF-kB in acute colitis with a Bcl family inhibitor. These findings are in line with the reported antiapoptotic properties of μORs in hepatocytes as a mechanism underlying the protective effect of μOR agonists in acute hepatitis in mouse [23]. Bcl-xL is a zinc finger protein of the bcl family involved in cell death regulation, which binds with and sequesters proapoptotic effectors, such as Bax, Raf-1 kinase or other factors, forming heterodimers that promote cell survival and protect tissue from injury-induced cell death [27, 28].…”

“…Upregulation of μOR mRNA has been reported in different animal models of intestinal inflammation [20, 21] and in patients with inflammatory bowel disease (IBD) [22], whereas μOR mRNA expression was impaired in chronic hepatitis [23]. Furthermore, activation of μORs with selective agonists has been shown to protect from intestinal inflammation induced by ischemia/reperfusion[24], prevent acute hepatitis [23] and ameliorate acute experimental colitis induced by intrarectal 2,4,6-trinitrobenzebesulfonic acid (TNBS) [20]. …”

Influence of Endogenous Opioid Systems on T Lymphocytes as Assessed by the Knockout of Mu, Delta and Kappa Opioid Receptors

“…This TH2-prone phenotype in T-OpR mice may appear in contrast with previous literature showing that acute and chronic morphine administration (Lockwood et al 1996;Sacerdote et al 1997Sacerdote et al , 2000West et al 1997;Roy et al 2001bRoy et al , 2004Saurer et al 2004), mu opioid peptide injection (Chakass et al 2007), and heroin addiction (Azarang et al 2007) resulted in a Th2 biased immune response. In contrast also, acute or chronic treatment with the general opioid antagonist naltrexone decreased TH2 and/or augmented TH1 responses (Sacerdote et al , 2000(Sacerdote et al , 2003Jazani et al 2010;Kelschenbach et al 2005), while chronic naloxone-methiodide augmented both IFNγ and IL-4 in mouse colon (Philippe et al 2003).…”

The Inflammatory Response to Cigarette Smoking Versus Inhaled Opium in the Liver: An Experimental Study

“…The findings about the triggering or inhibitory effects of opiates on inflammation systems are now conflicting. Although some studies emphasized anti-inflammatory effects of some opiates such as morphine [20], some others showed that the dual effect of opium on inflammation might be dependant to the type of the opioid receptors in the especial organs [21], that µ opioid receptor activation prevents acute hepatic inflammation and cell death and activation of the δ-opioid receptor inhibits serum deprivation induced apoptosis of human liver cells via the activation of PKC (protein kinase C) and the mitochondrial pathway [22,23], while some studies showed that administration of opioid receptors antagonists attenuate liver fibrosis [24]. Thus, impact of opium on liver inflammation systems should be assessed considering the types of activated opiate receptors in liver tissue.…”