• Alexander Samoshkin, Marino Convertino, Chi T Viet, Jeffrey S Wieskopf, Oleg Kambur, Jaclyn Marcovitz, Pinkal Patel, Laura S Stone, Eija Kalso, Jeffrey S Mogil, Brian L Schmidt, William Maixner, Nikolay V Dokholyan, and Luda Diatchenko.
• Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.
• Sci Rep. 2015 Dec 11; 5: 18198.

AbstractThe 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.

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