Abstract
Lithocholic acid (LCA) deposited in human livers always induces drastic pains which need analgesic drug, like morphine to release. Our research showed that LCA can effectively inhibit uridine 5’-diphospho-glucuronosyltransferase 2B7 (UGT2B7) in morphine tolerance-like human normal liver cells, HL-7702, then increase μ-opioid receptor (MOR) and calcium–calmodulin dependent protein kinase IIα (CaMKIIα) expression. In vivo assay, UGT2B7 was significantly repressed in the livers of acute or chronic morphine tolerance mice pretreated with LCA (10, 50, and 100 mg/kg, p.o.). To investigate the connections between LCA function performance and change of UGT2B7 enzymatic activity in mice livers, two morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were quantified by solid phase extraction (SPE)–HPLC–MS/MS. The result indicated no matter in acute or chronic morphine tolerance, the concentrations of M3G and M6G were all decreased, the later one fell even more. Besides that, 50 mg/kg of LCA administration can prevent auto-phosphorylation of CaMKIIα at Thr286 in acute or chronic morphine tolerance mice prefrontal cortexes (mPFCs) due to synthesis increase of cyclic adenosine monophosphate. As a consequence, UGT2B7 depression mediated by LCA can affect its selective catalysis ability to morphine, that may be responsible to acute or chronic morphine tolerance alleviation. These findings might assist to modify antinociception of morphine in clinic.
Highlights
Bile acids deposited in livers of patients mainly occurs in primary biliary cirrhosis (PBC), and accompanies with many complications, such as hepatic failure (Vlahcevic et al, 1981; Ishibashi et al, 2011; Jankowska and Socha, 2012)
The results indicated that MOR decreased significantly compared to control group, the morphine tolerance-like status was induced in HL-7702 cells (Figure 1A)
In order to investigate the effect of lithocholic acid (LCA) on uridine 5’-diphospho-glucuronosyltransferase 2B7 (UGT2B7) expression, HL7702 cells were treated with different concentrations of LCA (10, 50, 100 μM) for 48 h, the cells were co-incubated with 1 μM morphine for another 48 h
Summary
Bile acids deposited in livers of patients mainly occurs in primary biliary cirrhosis (PBC), and accompanies with many complications, such as hepatic failure (Vlahcevic et al, 1981; Ishibashi et al, 2011; Jankowska and Socha, 2012). As one of vital secondary bile acids derived from primary chenodeoxycholic (CDCA) (de Paiva et al, 2015), lithocholic acid (LCA) is regarded as a main index to diagnose hepatic diseases (Lucangioli et al, 2009) which can be increased significantly in PBC induced extrahepatic cholestasis (Ceryak et al, 1998). To better control and release the pain, some opioid analgesic drugs were preferably used in clinic practice. Accompanying with their applications, tolerance would come into being
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