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 language | English (US) |
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Article number | 2405 |
Journal | Scientific reports |
Volume | 9 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2019 |
Bibliographical note
Funding Information:This work was supported by grants 103-2325-B-400-018, 104-2325-B-400-008, 105-2325-B-400-007, and 101-2311-B-400-005-MY3 obtained from the Ministry of Science and Technology, and Intramural Research Program of National Health Research Institutes, Taiwan.
Publisher Copyright:
© 2019, The Author(s).