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. LINKED ARTICLESThis 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

Involvement of Opioid Receptors and α2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study

“…34 It seems unlikely, however, that peripheral processes involving these receptors mediated ipsilateral analgesia in the forehead after HFS, due (i) to the degree of separation between the site of stimulation (the forearm) and analgesia effectiveness of tapentadol, a combined µ-opioid receptor agonist and noradrenaline reuptake inhibitor. 6,37,44 However, our findings suggest that analgesia to blunt pressure in the forehead was mediated primarily by opioid receptors as, in our previous work, yohimbine alone was ineffective. 51 …”

Heterologous Regulation of Mu-Opioid (MOP) Receptor Mobility in the Membrane of SH-SY5Y Cells

“…2) and are not known to form heterodimers with MOP receptors (66), have no effect on the diffusion of the MOP receptor. Because NPY receptors activate the same type of G protein as NPFF 2 and ␣ 2 -adrenergic receptors, this means that triggering G i/o signaling is not sufficient to modify MOP receptor dynamics. Therefore, knowing that agonists induce heterodimer formation between MOP receptors and ␣ 2 -adrenergic (13) and NPFF 2 receptors (18), our results suggest that heterologous regulation of the MOP receptor through heteromerization impacts its dynamic organization in the membrane.…”

“…The cellular and pharmacological activities of the MOP receptor are modulated by other GPCR systems (2)(3)(4)(5). In some case, such heterologous regulation involves receptor heteromerization (6), which is considered to confer new binding and endocytosis properties to the complex and/or to promote novel signaling pathways or, conversely, to impair signal transduction (7,8).…”

Methadone and Dexmedetomidine Combination as Premedicant Agents for Ovariectomy in Cats

“…In rodents, co-administration of opioid and alpha 2 agonists can produce "greater-than-additive" (i.e., synergistic) analgesic effects (Chabot-Doré et al, 2014).…”

“…Such interaction could occur at primary afferent neurons level, the spinal cord and the other sites in the CNS, as well as in the periphery (Jordan, et al, 2003). Although these studies were all performed in rodents, there is no indication that opioidadrenoceptor interactions are subject to species differences (Chabot-Doré et al, 2014). These effects may be achieved at much lower doses of alpha 2 agonist because of additive or synergistic effects of the two agents (Ossipov et al, 1990).…”