title: Analgesic synergy between opioid and α2 -adrenoceptors.
abstract: Opioid and α2 -adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2 -adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2 -adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2 -adrenoceptor agonists and that α2 -adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid-adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors.forename: A-J
authors.initials: AJ
authors.lastname: Chabot-Doré
authors.forename: D J
authors.initials: DJ
authors.lastname: Schuster
authors.forename: L S
authors.initials: LS
authors.lastname: Stone
authors.forename: G L
authors.initials: GL
authors.lastname: Wilcox
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004357:Drug Synergism; D006801:Humans; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D000316:Adrenergic alpha-Agonists; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid
keywords: analgesia; spinal; synergy; α2-adrenoceptors; δ opioid receptor; μ opioid receptor