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Neuropharmacology. 2015 Dec;99:285-300. doi: 10.1016/j.neuropharm.2015.08.010. Epub 2015 Aug 6.

Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.

Author information

1
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada. Electronic address: anne-julie.chabot-dore@mail.mcgill.ca.
2
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada. Electronic address: magali.millecamps@mcgill.ca.
3
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada. Electronic address: lina.naso@mcgill.ca.
4
Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: dominic.devost@mcgill.ca.
5
Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: phan.trieu@mcgill.ca.
6
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada. Electronic address: marjo.piltonen@mail.mcgill.ca.
7
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: luda.diatchenko@mcgill.ca.
8
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: carfair@umn.edu.
9
Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA; Department of Dermatology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: george@umn.edu.
10
Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: terence.hebert@mcgill.ca.
11
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: laura.s.stone@mcgill.ca.

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.

KEYWORDS:

Analgesia; Morphine; Norepinephrine; Opioid receptor; Spinal cord; α(2-)adrenoceptor

PMID:
26254859
PMCID:
PMC4655173
DOI:
10.1016/j.neuropharm.2015.08.010
[Indexed for MEDLINE]
Free PMC Article

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