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

• Published in: Scientific reports Vol. 9; no. 1; p. 2405
• Main Authors: Chao, Po-Kuan, Chang, Hsiao-Fu, Ou, Li-Chin, Chuang, Jian-Ying, Lee, Pin-Tse, Chang, Wan-Ting, Chen, Shu-Chun, Ueng, Shau-Hua, Hsu, John Tsu-An, Tao, Pao-Luh, Law, Ping-Yee, Loh, Horace H., Yeh, Shiu-Hwa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2019; Nature Publishing Group
• Subjects: 13/51; 13/89; 14/19; 42/44; 45/47; 631/154/436/2387; 631/378/1689; 64/60; 82; 96/35; Analgesia; Analgesia - methods; Analgesics; Analgesics - chemistry; Analgesics - pharmacology; Animal models; Animals; Clathrin; Disease Models, Animal; Drug tolerance; Endocytosis; Endocytosis - drug effects; High-throughput screening; Humanities and Social Sciences; Humans; Hyperpolarization; Inflammation; Ligands; Mice; Morphine; Morphine - pharmacology; multidisciplinary; Narcotics; Opioid receptors (type mu); Pain perception; Phosphorylation; Receptors, Opioid, mu - drug effects; Receptors, Opioid, mu - genetics; Science; Science (multidisciplinary); Side effects; Strophanthins - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-39555-x

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.