Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice

Po Kuan Chao, Hsiao Fu Chang, Li Chin Ou, Jian Ying Chuang, Pin Tse Lee, Wan Ting Chang, Shu Chun Chen, Shau Hua Ueng, John Tsu An Hsu, Pao Luh Tao, Ping Yee Law, Horace H. Loh, Shiu Hwa Yeh

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2 Scopus citations

Abstract

Morphine is a unique opioid analgesic that activates the mu-opioid receptor (MOR) without efficiently promoting its endocytosis that may underlie side effects. Our objective was to discover a novel enhancer of ligand-induced MOR endocytosis and determine its effects on analgesia, tolerance and dependence. We used high-throughput screening to identify convallatoxin as an enhancer of ligand-induced MOR endocytosis with high potency and efficacy. Treatment of cells with convallatoxin enhanced morphine-induced MOR endocytosis through an adaptor protein 2 (AP2)/clathrin-dependent mechanism, attenuated morphine-induced phosphorylation of MOR, and diminished desensitization of membrane hyperpolarization. Furthermore, co-treatment with chronic convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance and dependence in morphine-tolerant mice. These findings suggest convallatoxin are potentially therapeutic for morphine side effects and open a new avenue to study MOR trafficking.

Original languageEnglish (US)
Article number2405
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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    Chao, P. K., Chang, H. F., Ou, L. C., Chuang, J. Y., 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., & Yeh, S. H. (2019). Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Scientific reports, 9(1), [2405]. https://doi.org/10.1038/s41598-019-39555-x