Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice
| Autor: | John Tsu An Hsu, Hsiao Fu Chang, Shu Chun Chen, Pin Tse Lee, Po Kuan Chao, Li Chin Ou, Jian Ying Chuang, Horace H. Loh, Wan Ting Chang, Ping-Yee Law, Shau-Hua Ueng, Pao-Luh Tao, Shiu Hwa Yeh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Receptors Opioid mu lcsh:Medicine Convallatoxin Pharmacology Ligands Endocytosis Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Strophanthins mental disorders polycyclic compounds medicine Animals Humans lcsh:Science Receptor Desensitization (medicine) Analgesics Multidisciplinary Morphine Chemistry lcsh:R Membrane hyperpolarization Disease Models Animal 030104 developmental biology Nociception nervous system lcsh:Q Analgesia μ-opioid receptor human activities 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-39555-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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