Martine delayed morphine tolerance associated with inhibited the expression of permeability-glycoprotein

Abstract

Objective The matrine(Mat)on the development of morphine tolerance was investigated in rats. Methods Established morphine tolerance rat model treated with Mat and morphine using the tail-flick test to assesse the degree of tolerance. The expression of morphine-induced multidrug resistance (MDR)1 and Permeability-glycoprotein (P-gp) was tested by reverse transcriptase-polymerase chain reaction (RT-PCR)/Western blotting analysis. Further synthesized in vitro with cyclic adenosine monophosphate (cAMP) response element sequence, using electrophoretic mobility shift assay (EMSA) detection of MDR1 gene upstream start cyclic adenosine monophosphate response element binding protein (CREB) DNA binding activity changes. Results Morphine tolerance model is established after 7 days, Mat (300 mg/kg) inhibited the development of morphine tolerance which decreased (6.71±0.27) s, MPE%: 42.1%, areas under the curve (AUC) ratio: 1.93 and ED50 effective threshold: (4.15±0.54) mg/kg were all below the morphine group (P<0.05). MDR1 mRNA and P-gp expression was decreasedin Mat (300 mg/kg) with morphine group (P<0.05), but the difference between the samples of each has statistical significance. Mat doesn't affect CREB DNA binding activity. Conclusion These results suggest that Mat is likely not only can enhance morphine's analgesic effects, but also has analgesic effects itself, which the mechanism was related to the inhibition of MDR1 mRNA/P-gp expression. Key words: Matrine; Morphine tolerance; Permeability-glycoprotein; Multidrug resistance