Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors

NEUROPHARMACOLOGY

卷:99

Article

Chabot-Dore, Anne-Julie^1,2  Millecamps, Magali^1,3  Naso, Lina^1,3  Devost, Dominic⁵  Trieu, Phan⁵  Piltonen, Marjo^1,3  Diatchenko, Luda^1,3,4  Fairbanks, Carolyn A.^6,7,8  Wilcox, George L.^7,8,9  Hebert, Terence E.⁵  Stone, Laura S.^1,2,3,4,5 

[1] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 0G1, Canada

[2] McGill Univ, Integrated Program Neurosci, Montreal, PQ H3A 0G1, Canada

[3] McGill Univ, Fac Dent, Montreal, PQ H3A 0G1, Canada

[4] McGill Univ, Fac Med, Dept Anesthesiol, Montreal, PQ H3A 0G1, Canada

[5] McGill Univ, Fac Med, Dept Pharmacol & Therapeut, Montreal, PQ, Canada

[6] Univ Minnesota, Coll Pharm, Dept Pharmaceut, Minneapolis, MN 55455 USA

[7] Univ Minnesota, Sch Med, Dept Neurosci, Minneapolis, MN 55455 USA

[8] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA

[9] Univ Minnesota, Sch Med, Dept Dermatol, Minneapolis, MN 55455 USA

关键词: alpha(2)-adrenoceptor;    Opioid receptor;    Norepinephrine;    Spinal cord;    Morphine;    Analgesia;   

DOI  :  10.1016/j.neuropharm.2015.08.010

来源: Elsevier

【 摘 要 】

Opioid and alpha(2)-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, alpha(2)-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The alpha(2A)-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the alpha(2A)-AR. Drugs were administered intrathecally in wild type (WT) and alpha(2A)-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The alpha(2A)-AR agonist clonidine was less effective in alpha(2A)-KO mice in both assays. The absence of the alpha(2A)-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltIL In contrast, neither morphine nor Deltll synergized with clonidine in alpha(2A)-KO mice, indicating that the alpha(2A)AR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-0HDA resulted in a significant decrease in morphine efficacy in WT but not in alpha(2A)-KO mice, suggesting that endogenous norepinephrine acts through the alpha(2A)-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free alpha(2A)-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied alpha(2A)-ARs potentiate opioid analgesia, while non-occupied alpha(2A)-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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