Inhibition of endothelin A receptor by a novel, selective receptor antagonist enhances morphine-induced analgesia: Possible functional interaction of dimerized endothelin A and μ-opioid receptors
| Autor: | Tetsushi Dodo, Keisuke Yamaguchi, Akane Komatsu, Kanako Miyano, Yasuhito Uezono, Yuji Kamikubo, Takashi Murayama, Masakazu Hayashida, Miki Nonaka, Haruo Ogawa, Nagomi Kurebayashi, Yui Kuroda, Masako Iseki, Takashi Sakurai, Kyoko Nakano-Ito, Hakushun Sakairi |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.drug_class Endothelin A Receptor Antagonists Analgesic Receptors Opioid mu Pain RM1-950 Pharmacology Peptides Cyclic 03 medical and health sciences Mice 0302 clinical medicine Opioid receptor medicine Animals Humans G protein-coupled receptor Receptor heterodimerization Receptor Pain Measurement Dose-Response Relationship Drug Morphine Chemistry General Medicine Receptor antagonist Receptor Endothelin A Bosentan Analgesics Opioid Mice Inbred C57BL 030104 developmental biology HEK293 Cells Opioid 030220 oncology & carcinogenesis Endothelin A receptor antagonist Therapeutics. Pharmacology Protein Multimerization medicine.drug |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 141, Iss, Pp 111800-(2021) |
| ISSN: | 1950-6007 |
| Popis: | Background The misuse of opioids has led to an epidemic in recent times. The endothelin A receptor (ETAR) has recently attracted attention as a novel therapeutic target to enhance opioid analgesia. We hypothesized that endothelin A receptors may affect pain mechanisms by heterodimerization with μ opioid receptors. We examined the mechanisms of ETAR-mediated pain and the potential therapeutic effects of an ETAR antagonist, Compound-E, as an agent for analgesia. Methods Real-time in vitro effect of Compound-E on morphine response was assessed in HEK293 cells expressing both endothelin A and μ opioid receptors through CellKey™ and cADDis cAMP assays. Endothelin A/μ opioid receptor dimerization was assessed by immunoprecipitation and live cell imaging. The in vivo effect of Compound-E was evaluated using a morphine analgesia mouse model that observed escape response behavior, body temperature, and locomotor activity. Results In CellKey™ and cAMP assays, pretreatment of cells with endothelin-1 attenuated morphine-induced responses. These responses were improved by Compound-E, but not by BQ-123 nor by bosentan, an ETAR and endothelin B receptor antagonist. Dimerization of ETARs and μ opioid receptors was confirmed by Western blot and total internal reflection fluorescence microscopy in live cells. In vivo, Compound-E potentiated and prolonged the analgesic effects of morphine, enhanced hypothermia, and increased locomotor activity compared to morphine alone. Conclusion The results suggest that attenuation by endothelin-1 of morphine analgesia may be caused by dimerization of Endothelin A/μ opioid receptors. The novel ETAR antagonist Compound-E could be an effective adjunct to reduce opioid use. |
| Databáze: | OpenAIRE |
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