Table 1.
Identification, downstream signaling, and function of Mu opioid receptor heterodimers in vitro and in vivo.
| Receptor pair | Tissue distribution | Methods | Ligand binding, downstream signaling and trafficking | Behavioral outcomes | References |
|---|---|---|---|---|---|
| MOR-DOR | Mouse brain, SC, DRG | Co-IP, disruptive peptides | Positive binding cooperativity, increased G protein signaling | ND | (Erbs et al., 2015) |
| Rat NRM | Whole-cell recording, behavioral test | Synergy upon co-activation of MOR and DOR | Increased analgesia | (Zhang and Pan, 2010) | |
| Rat RVM | Behavioral test | Synergy upon co-activation of MOR and DOR | Increased analgesia | (Sykes et al., 2007) | |
| DRG | Electrophysiological recording | Inhibitory coupling of MOR to VDCCs | ND | (Walwyn et al., 2009) | |
| DRG | Co-IP, disruptive peptides | DOR phosphorylation at Thr-161 is required for the formation of DOR-MOR heterodimers | Morphine analgesic tolerance | (Xie et al., 2009) | |
| DRG, SC | Co-IP, disruptive peptides | DOR activation led to endocytosis and degradation of surface MOR | Disrupted MOR-DOR enhanced morphine analgesia and reduced morphine tolerance | (He et al., 2011) | |
| SC | Co-IP, BRET | DOR antagonists enhance MOR binding and signaling activity | DOR antagonists enhance morphine analgesia | (Gomes et al., 2004) | |
| brain | Antibody to MOR-DOR heterodimers, heterodimer biased ligand (CYM51010) | MOR-DOR co-internalization | CYM51010 induced analgesia similar to morphine, but less analgesic tolerance | (Gomes et al., 2013) | |
| Striatum, hippocampus | Deltorphin-II | Gαz activation, and no uncoupling after chronic morphine | ND | (Kabli et al., 2014) | |
| DRG | Co-localization, Deltorphin-II | DAMGO induced DOP receptor internalization and trafficking following chronic morphine | ND | (Ong et al., 2015) | |
| Brain | Antibody to MOR-DOR heterodimers | Increased MOR-DOR abundance following chronic morphine | ND | (Gupta et al., 2010) | |
| Brain, DRG, SC | Co-IP, redMOR/greenDOR double knock-in mice | MOR and DOR neuronal co-expression in dorsal root ganglia, spinal cord, hippocampus, LH, basal nucleus of Meynert, and piriform cortex. | ND | (Scherrer et al., 2009) | |
| Brain, SC | DORGFP mice and MORmCherry mice | DOR and MOR is limited to small populations of the spinal cord and is rare in parabrachial, amygdalar, and cortical brain regions related to pain. | ND | (Wang et al., 2018) | |
| DRG | ISH, single-cell PCR, immunostaining | Coexistence of DORs and MORs in small DRG neurons; Both DOR and MOR agonists reduce Ca2+ currents in DRG neurons and inhibit C-fiber synaptic transmission in the spinal cord. | ND | (Wang et al., 2010) | |
| MOR-KOR | Rat SC in female | Co-IP, cross-linking experiments | Synergy upon co-activation of MOR and KOR | Spinal morphine analgesia in female | (Chakrabarti et al., 2010) |
| MOR-CB1 | Rat striatum | Electron microscopic immunocytochemical labeling | MOR and CB1 are partially colocalized in dendrites in striatum | ND | (Rodriguez et al., 2001) |
| Striatum | BRET | Reciprocal cross antagonism | Co-activation of MOR and CB1 receptors leads to a attenuation of the response upon activation of individual receptors for neuritogenesis | (Rios et al., 2006) | |
| Rat or mouse NAcC | Behavioral, pharmacological, electrophysiological methods | Bidirectional negative crosstalk | Co-activation of MOR and CB1 receptors increased social play behaviors | (Manduca et al., 2016) | |
| MOR-Gal1R | Mouse VTA | BRET, BiFC, disrupting synthetic peptide | Cross-antagonistic interactions between MOR and Gal1R | Opioids-induced reward | (Moreno et al., 2017) |
| Mouse VTA | BRET, microdialysis, [18F]FDG PET imaging. | MOR-Gal1R attenuates the potency of methadone, but not other opioids, in stimulating the dopamine release in the VTA | Opioids-induced euphoria | (Cai et al., 2019) | |
| MOR-alpha2A | Hippocampal neurons | Co-IP, BRET, | Activation of either MOR or alpha2A receptors leads to an increase in the extent of signaling, whereas activation of both receptors leads to a decrease. | ND | (Tan et al., 2009) |
| Rat NTS | Co-IP, In situ proximity ligation assays, immunofluorescence staining | MOR-alpha2A reduced the NO-dependent depressor effects of activation of alpha2A receptor. | Hypertension | (Sun et al., 2015) | |
| FRET | Cross-inhibition upon agonist coactivation | ND | (Vilardaga et al., 2008) | ||
| MOR-GPR139 | Mouse brain, including VTA, PAG, CPu, and DRG | ISH, co-IP, | Increased β-arrestin signaling, inhibition of G protein signaling, impede MOR trafficking to the cell surface | Diminished morphine analgesia, suppressed morphine self-administration | (Wang et al., 2019) |
| MOR-CCR5 | Human and monkey lymphocytes | Co-IP, chemical crosslinking experiments | Combination treatment of cells with morphine, an agonist for mu, and MIP-1beta, a ligand for CCR5, suppresses the inhibitory effect of MIP-1beta and increases the stimulatory effect of morphine on CCR5 expression. | ND | (Suzuki et al., 2002) |
| Rat PAG | Behavioral tests | Activation of CCR5 led to desensitization of MOR | Activation of MOR-CCR5 increased nociception | (Szabo et al., 2002) | |
| MOR-CCKBR | Rat SC and DRG | Co-IP, FLIM-FRET, MOR mutant construction, cell-penetrating interfering peptide | Weakened the activity of MOR | CCK-8 antagonism to morphine analgesia in rats | (Yang et al., 2018) |
| MOR-V1bR | Mouse RVM | ISH, co-IP, BRET, Truncated V1bR receptor, genome editing | Increased β-arrestin-2 signaling, upregulation of ERK phosphorylation and adenylate cyclase sensitization | Morphine analgesic tolerance | (Koshimizu et al., 2018) |
| MOR1D-GRPR | Mouse SC | Co-IP, disruptive peptide | Cross-activate GRPR signaling, including PLCβ3 and IP3R3 signaling. | I.t. injection of morphine-induced itch in mice | (Liu X. Y. et al., 2011) |
BiFC, Bimolecular fluorescence complementation; BRET, bioluminescence resonance energy transfer; CCKBR, cholecystokinin type B receptor; CCR5, C-C chemokine receptor type 5; Co-IP, Co-immunoprecipitation; CPu, Caudate Putamen; DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DRG, Dorsal Root Ganglion; FLIM-FRET, fluorescence lifetime-imaging-microscopy-based fluorescence resonance energy transfer; Gal1R, galanin-1 receptor; ISH, in situ hybridization; LH, lateral hypothalamus; NAcC, nucleus accumbens core; ND, not determined; NRM, nucleus raphe magnus; NTS, nucleus tractus solitarii; PAG, Periaqueductal Gray; PET, positron emission tomography; RVM, rostral ventromedial medulla; V1bR, vasopressin 1b receptors; VDCCs, voltage-dependent calcium channels; VTA, Ventral Tegmental Area.