Table 3.

Heteromers involving opioid receptors and GPCRs other than cannabinoid or catecholamine receptors^a

Heteromer pair	In vitro heteromer properties (binding, signalling, trafficking)	In vivo effects of reagents targeting heteromers	References
δ-CXCR4	Detection Co-IP, FRET Binding No change. Signalling Inactivated by δ + CXCR4 agonists. No association with G-proteins in the presence of δ + CXCR4 agonists. Trafficking No change.		Pello et al., 2008
δ-SNSR-4	Detection BRET Binding Remains to be determined Signalling Preferential Gαq signalling and attenuation of Gαi signalling. Trafficking ↓ in δ receptor endocytosis by BAM22 in the presence of SNSR-4.		Breit et al., 2006
κ-APJ	Detection Colocalization, Co-IP, BRET Binding Remains to be determined. Signalling ↑ in heteromer-mediated PKC signalling. Trafficking Remains to be determined.		Li et al., 2012
μ-CCR5b2002	Detection Co-IP Binding Binding affinity for a ligand to one protomer not changed in the presence of ligand to partner protomer. Signalling ↓ in μ receptor -mediated G-protein activation by CCR5 receptor agonist and vice versa. Trafficking μ receptor internalization by μ and not by CCR5 receptor agonists and vice versa.	Bivalent ligand (Bivalent ligand 1) More potent inhibition of viral entry compared with naltrexone + maraviroc in antiviral activity assay.	Suzuki et al., 2002; Chen et al., 2004; Yuan et al., 2012; 2013
μ1D-GRPRc2002	Detection Co-IP Binding Not reported. Signalling μ receptor-mediated Ca+2 signalling only in cells expressing the heteromer. Trafficking ↑ in μ receptor -mediated GRPR internalization.	TAT-fusion protein (TAT-μ1DCT) TAT-μ1DCT disrupts μ1D-GRP receptor heteromers and blocks morphine-induced scratching without affecting analgesia.	Liu et al., 2011
μ-mGlu5d2002	Detection Co-IP Binding No change in binding affinity for μ receptor agonist. ↑ in binding affinity for mGlu5 receptor antagonist. Signalling No change in μ receptor agonist-mediated inhibition of adenylate cyclase activity. mGlu5 receptor antagonist ↓ μ receptor agonist-mediated phosphorylation and desensitization of μ receptors. Trafficking mGlu5 receptor antagonist ↓ μ receptor agonist-mediated internalization of μ receptors.	Bivalent ligand (MMG22) MMG22 antinociception (i.t. and i.c.v.) is equipotent to morphine in naïve mice, and more potent in LPS-treated mice with less tolerance and respiratory depression. MMG22 shows antinociception (i.t.) in CFA-induced inflammatory pain or bone cancer pain model.	Schroder et al., 2009; Akgun et al., 2013
μ-5-HT1A	Detection Colocalization, Co-IP, BRET Binding Remains to be determined. Signalling Transactivation of G-protein fused to 5-HT1A receptor by μ receptor agonist. Activation of ERK1/2 by μ receptor agonist is blocked by 5-HT1A receptor agonist pretreatment. Trafficking No co-internalization by protomer-selective agonists.		Daval et al., 1987; Pompeiano et al., 1992; Wang et al., 1998; Zhang et al., 2000; Kishimoto et al., 2001; Cussac et al., 2012
μ-NK1d2002	Detection Colocalization, Co-IP, BRET Binding ↑ in affinity for μ receptor agonist. No change in affinity for NK1 receptor agonist. Signalling Pre-incubation with μ agonist ↓ NK1 receptor-mediated ERK phosphorylation and vice versa. Trafficking Co-internalization by protomer-selective agonists.	Bivalent peptide Assay shows that the peptide exhibits μ agonist and NK1 receptor antagonist activity. Small molecule ligands Assay shows that the ligands exhibit μ agonist and NK1 receptor antagonist activity. Multifunctional μ/δ agonist/NK1 receptor antagonist compound (TY027) TY027 exhibits antinociception (i.c.v., i.t.) in naïve mice. TY027 exhibits antinociception (i.t., i.v.) against spinal nerve ligation-induced hyperalgesia. TY027 produced antinociception with low tolerance, dependence or rewarding effects and was not accompanied by opioid-related emesis or constipation.	Aicher et al., 2000a,b; Pfeiffer et al., 2003; Yamamoto et al., 2007; Vardanyan et al., 2011; Largent-Milnes et al., 2013
μ-sst2A	Detection Colocalization, Co-IP Binding ↓ in binding affinity for sst2 receptor agonists. No change in binding affinity for μ receptor agonist. Signalling ↑ inhibition of adenylate cyclase activity. No change in ERK1/2 activation. Pretreatment with the protomer agonist causes cross-desensitization. Trafficking sst2 receptor agonist induces heteromer internalization. μ agonist internalizes μ receptors but not sst2A receptors.		Pfeiffer et al., 2002

^aModified from (Gomes et al., 2013a).

^b,c,dThese heteromers are useful therapeutic targets, based on the known roles of one or both protomers. Therapeutic targets: ^bAntiviral activity; ^cMorphine-induced itch; ^dAntinociception.