title: Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.
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.
authors.affiliation: 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.
authors.forename: Anne-Julie
authors.initials: AJ
authors.lastname: Chabot-Doré
authors.affiliation: 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.
authors.forename: Magali
authors.initials: M
authors.lastname: Millecamps
authors.affiliation: 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.
authors.forename: Lina
authors.initials: L
authors.lastname: Naso
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: dominic.devost@mcgill.ca.
authors.forename: Dominic
authors.initials: D
authors.lastname: Devost
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: phan.trieu@mcgill.ca.
authors.forename: Phan
authors.initials: P
authors.lastname: Trieu
authors.affiliation: 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.
authors.forename: Marjo
authors.initials: M
authors.lastname: Piltonen
authors.affiliation: 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.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: 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.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
authors.affiliation: 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.
authors.forename: George L
authors.initials: GL
authors.lastname: Wilcox
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: terence.hebert@mcgill.ca.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hébert
authors.affiliation: 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.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000494:Allosteric Regulation; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P
chemical_list: C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D013373:Substance P; D003000:Clonidine
keywords: Analgesia; Morphine; Norepinephrine; Opioid receptor; Spinal cord; α(2-)adrenoceptor