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.

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