Dual allosteric modulation of opioid antinociceptive potency by alpha(2A)-adrenoceptors

作者：Chabot Dore Anne Julie; Millecamps Magali; Naso Lina; Devost Dominic; Trieu Phan; Piltonen Marjo; Diatchenko Luda; Fairbanks Carolyn A; Wilcox George L; Hebert Terence E; Stone Laura S

来源：Neuropharmacology, 2015, 99: 285-300.

DOI：10.1016/j.neuropharm.2015.08.010

• alpha(2)-adrenoceptor
• Opioid receptor
• Norepinephrine
• Spinal cord
• Morphine
• Analgesia

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.

• 出版日期2015-12