Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities

Abstract

Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands.

Linked articles: 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.

Keywords: antinociception; dependence; heteromer; high-throughput screening; opioid; signalling; tolerance; trafficking.

Figure 1

High-throughput screening assay for heteromer-selective ligands using cells expressing DOP^βgal receptor, MOP^βgal receptor or MOP^βgal-DOP receptor. (A & B) Schematics of monomer or homomer-mediated β-arrestin recruitment. Treatment of cells expressing either DOP receptor (DOPr) (A) or MOP receptor (MOPr) (B) tagged with ProLink/β-galactosidase donor (PK) (DOP^βgal receptor and MOP^βgal receptor, respectively) and β-arrestin (β−Arr-EA) tagged with a β-galactosidase activator (EA) with receptor-selective agonists leads to recruitment of β-arrestin to the receptor and reconstitution of a functionally active β-galactosidase whose activity can be measured by addition of an enzyme-specific substrate. (C) Schematic of heteromer-mediated β-arrestin recruitment. Treatment of cells expressing untagged DOP receptor and MOP receptor tagged with ProLink/β-galactosidase donor (PK) (MOP^βgal-DOP receptor) and β-arrestin tagged with a β-galactosidase activator (EA) with a DOP receptor-selective agonist leads to recruitment of β-arrestin to MOP receptor and reconstitution of a functionally active β-galactosidase whose activity can be measured by addition of an enzyme-specific substrate, only if both receptors form interacting complexes. Modified from Gomes et al. (2013b).