Drug discovery to counteract antinociceptive tolerance with mu-opioid receptor endocytosis

Chao, P.-K.; Ke, Y.-Y.; Chang, H.-F.; Huang, Y.-H.; Ou, L.-C.; Chuang, J.-Y.; Lin, Y.-C.; Lee, P.-T.; Chang, W.-T.; Chen, S.-C.; Ueng, S.-H.; Hsu, J. T.-A.; Tao, P.-L.; Law, P.-Y.; Loh, H. H.; Shih, C.; Yeh, S.-H.

doi:10.1101/182360

bioRxiv · 10.1101/182360

Drug discovery to counteract antinociceptive tolerance with mu-opioid receptor endocytosis

Chao, P.-K.·Ke, Y.-Y.·Chang, H.-F.·Huang, Y.-H.·Ou, L.-C.·Chuang, J.-Y.·Lin, Y.-C.·Lee, P.-T.·Chang, W.-T.·Chen, S.-C.·Ueng, S.-H.·Hsu, J. T.-A.·Tao, P.-L.·Law, P.-Y.·Loh, H. H.·Shih, C.·Yeh, S.-H.

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Abstract

Morphine antinociceptive tolerance is highly correlated with its poor ability to promote mu-opioid- receptor (MOR) endocytosis. Our objective was to discover a novel positive allosteric modulator of MOR to enhance morphine-induced MOR endocytosis. We used high-throughput screening to identify several cardiotonic steroids as positive allosteric modulators of morphine-induced MOR endocytosis having high potency and efficacy, independently of Na+/K+-ATPase inhibition. Convallatoxin was found to enhance morphine-induced MOR endocytosis through an adaptor protein 2/clathrin-dependent mechanism without regulating G protein- or {beta}-arrestin-mediated pathways. Both F243 and I292 residues of MOR were essential to the effect of convallatoxin on MOR endocytosis. Co-treatment with chronic morphine and convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance in morphine-tolerant mice. These findings suggest that cardiotonic steroids are potentially therapeutic for morphine side effects and open a new avenue for the study of MOR trafficking.

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Chao, P.-K., Ke, Y.-Y., Chang, H.-F., Huang, Y.-H., Ou, L.-C., Chuang, J.-Y., Lin, Y.-C., Lee, P.-T., Chang, W.-T., Chen, S.-C., Ueng, S.-H., Hsu, J. T.-A., Tao, P.-L., Law, P.-Y., Loh, H. H., Shih, C., Yeh, S.-H.. 2017-08-29. Drug discovery to counteract antinociceptive tolerance with mu-opioid receptor endocytosis. https://doi.org/10.1101/182360

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