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Sci Rep. 2015 Dec 11;5:18198. doi: 10.1038/srep18198.

Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling.

Author information

1
Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.
2
Department of Anesthesia, McGill University, Montreal, QC, H4A 3J1, Canada.
3
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA.
4
Bluestone Center for Clinical Research, New York University, New York, NY, 10010, USA.
5
Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
6
Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
7
Faculty of Dentistry, McGill University, Montreal, QC, H3A 1G1, Canada.
8
Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
9
Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, NC, 27599, USA.

Abstract

The primary molecular target for clinically used opioids is the μ-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 β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-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 β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-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 β2-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 β2-AR antagonists, providing a new avenue for opioid therapy.

PMID:
26657998
PMCID:
PMC4676002
DOI:
10.1038/srep18198
[Indexed for MEDLINE]
Free PMC Article

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