期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep18198
关键词
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资金
- Oral and Maxillofacial Surgery Research Support Grant [CERC09]
- Louise and Alan Edwards Foundation
- Pfizer Canada Professorship in Pain Research
- T90 training grant [1T90DE021986]
- Confocal and Multiphoton Imaging Core of NINDS Center [P30 NS045892]
- [P01 NS045685]
- [STTR 1R41DA032293]
- [R01DE019796]
The primary molecular target for clinically used opioids is the mu-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with beta(2)-adrenergic receptors (beta(2)-ARs) through an interaction with the fifth and sixth helices of beta(2)-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective beta(2)-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and beta(2)-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with beta(2)-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by beta(2)-AR antagonists, providing a new avenue for opioid therapy.
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