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Abstract
Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport. These findings might help to improve the pharmacological effects of morphine.
Highlights
IntroductionOne potential way is to reduce the accumulations of morphine and its metabolites in the brain by regulating their uptake or efflux
To repress morphine tolerance, one potential way is to reduce the accumulations of morphine and its metabolites in the brain by regulating their uptake or efflux
OATP2B1 substrates including atorvastatin, fluvastatin and E-3-S were used as positive controls to test the cell functions
Summary
One potential way is to reduce the accumulations of morphine and its metabolites in the brain by regulating their uptake or efflux. P-gp induction would reduce morphine’s pharmacologic activity by increasing morphine brain efflux in rats and play main role in suppression of morphine tolerance[12] Some researches referred both of M3G and M6G can be excreted by multidrug resistance protein 2 (MRP2, ABCC2) and multidrug resistance protein 3 (MRP3, ABCC3)[13]. Shyam et al used a linear polyethyleneimine (LPEI)-g-polyethylene glycol (PEG) copolymer micellar nanoparticle system to capsulate siRNA and effectively knock down BACE1 in heterogeneous tissues of mice[27] They found the nanoparticles decorated PEG can improve its brain-targeted capacity. Dermorphin is the identified aptamer, nearly 90 percent free styles of which can recognize MOR in brain parenchyma and obstructed by brain capillary endothelial cells[28] In previously research, such formulated nanoparticle has been applied to delivery shRNA to knock down Ask[1] in mice brains[29]. We selected it as brain-targeted carrier in this study to knock down OATP2B1 in mouse brain
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