Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors

Anne Julie Chabot-Doré, Magali Millecamps, Lina Naso, Dominic Devost, Phan Trieu, Marjo Piltonen, Luda Diatchenko, Carolyn A. Fairbanks, George L. Wilcox, Terence E. Hébert, Laura S. Stone

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Abstract Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-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 α2A-AR. Drugs were administered intrathecally in wild type (WT) and α2A-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The α2A-AR agonist clonidine was less effective in α2A-KO mice in both assays. The absence of the α2A-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in α2A-KO mice, indicating that the α2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in α2A-KO mice, suggesting that endogenous norepinephrine acts through the α2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free α2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied α2A-ARs potentiate opioid analgesia, while non-occupied α2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management.

Original languageEnglish (US)
Article number5956
Pages (from-to)285-300
Number of pages16
JournalNeuropharmacology
Volume99
DOIs
StatePublished - Aug 6 2015

Keywords

  • Analgesia
  • Morphine
  • Norepinephrine
  • Opioid receptor
  • Spinal cord
  • αadrenoceptor

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    Chabot-Doré, A. J., Millecamps, M., Naso, L., Devost, D., Trieu, P., Piltonen, M., Diatchenko, L., Fairbanks, C. A., Wilcox, G. L., Hébert, T. E., & Stone, L. S. (2015). Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors. Neuropharmacology, 99, 285-300. [5956]. https://doi.org/10.1016/j.neuropharm.2015.08.010