2. Academic Validation
  3. Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice

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

  • Sci Rep. 2019 Feb 20;9(1):2405. doi: 10.1038/s41598-019-39555-x.
Po-Kuan Chao 1,  Hsiao-Fu Chang 1,  Li-Chin Ou 1,  Jian-Ying Chuang 2,  Pin-Tse Lee 3,  Wan-Ting Chang 1,  Shu-Chun Chen 1,  Shau-Hua Ueng 1,  John Tsu-An Hsu 1,  Pao-Luh Tao 4,  Ping-Yee Law 5,  Horace H Loh 5,  Shiu-Hwa Yeh 6 7
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, 35053, Taiwan.
  • 2 The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, 110, Taiwan.
  • 3 Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD, 21224, USA.
  • 4 Center for Neuropsychiatric Research, National Heath Research Institutes, Zhunan, 35053, Taiwan.
  • 5 Department of Pharmacology, Medical School University of Minnesota, Minneapolis, MN, 55455-0217, USA.
  • 6 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, 35053, Taiwan. [email protected].
  • 7 The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, 110, Taiwan. [email protected].
PMID: 30787373 DOI: 10.1038/s41598-019-39555-x
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.

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