δ-opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein G_i/G₀ and has enkephalins as its endogenous ligands.^[5] The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.^[6]

OPRD1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4N6H, 4RWA, 4RWD
Identifiers
Aliases	OPRD1, OPRD, Δ-opioid receptor, opioid receptor delta 1, DOP, DOR1, DOR
External IDs	OMIM: 165195 MGI: 97438 HomoloGene: 20252 GeneCards: OPRD1
Gene location (Human) Chr. Chromosome 1 (human)^[1] Band 1p35.3 Start 28,812,170 bp^[1] End 28,871,267 bp^[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)^[2] Band 4 D2.3|4 64.78 cM Start 131,838,037 bp^[2] End 131,871,797 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell islet of Langerhans prefrontal cortex middle temporal gyrus superior frontal gyrus Brodmann area 23 dorsolateral prefrontal cortex Brodmann area 9 postcentral gyrus cingulate gyrus Top expressed in pituitary stalk secondary oocyte superior frontal gyrus outer nuclear layer inner nuclear layer cerebellar cortex globus pallidus trigeminal ganglion respiratory epithelium nose More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled enkephalin receptor activity G protein-coupled receptor activity neuropeptide binding signal transducer activity G protein-coupled opioid receptor activity protein binding receptor serine/threonine kinase binding peptide binding Cellular component cytoplasm axon terminus integral component of membrane vesicle postsynaptic membrane membrane intrinsic component of plasma membrane plasma membrane integral component of plasma membrane dendrite membrane membrane raft neuron projection integral component of synaptic vesicle membrane spine apparatus neuronal dense core vesicle integral component of presynaptic membrane integral component of postsynaptic density membrane Biological process regulation of calcium ion transport adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway regulation of sensory perception of pain eating behavior adult locomotory behavior negative regulation of protein oligomerization cellular response to growth factor stimulus G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger cellular response to toxic substance negative regulation of gene expression positive regulation of peptidyl-serine phosphorylation regulation of mitochondrial membrane potential phospholipase C-activating G protein-coupled receptor signaling pathway positive regulation of CREB transcription factor activity G protein-coupled opioid receptor signaling pathway immune response neuropeptide signaling pathway cellular response to hypoxia signal transduction chemical synaptic transmission sensory perception of pain G protein-coupled receptor signaling pathway cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4985 18386 Ensembl ENSG00000116329 ENSMUSG00000050511 UniProt P41143 P32300 RefSeq (mRNA) NM_000911 NM_013622 RefSeq (protein) NP_000902 NP_038650 Location (UCSC) Chr 1: 28.81 – 28.87 Mb Chr 4: 131.84 – 131.87 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The endogenous system of opioid receptors is well known for its analgesic potential; however, the exact role of δ-opioid receptor activation in pain modulation is largely up for debate. This also depends on the model at hand since receptor activity is known to change from species to species. Activation of delta receptors produces analgesia, perhaps as significant potentiators of μ-opioid receptor agonists. However, it seems like delta agonism provides heavy potentiation to any mu agonism. Therefore, even selective mu agonists can cause analgesia under the right conditions, whereas under others can cause none whatsoever.^[7][8] It is also suggested however that the pain modulated by the μ-opioid receptor and that modulated by the δ-opioid receptor are distinct types, with the assertion that DOR modulates the nociception of chronic pain, while MOR modulates acute pain.^[9]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep,^[10] but in tests on mice the non-peptide delta agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg.^[11] In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent μ-opioid agonist alfentanil, without affecting pain relief.^[12] It thus seems likely that while δ-opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.^[13]

Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects^[14] and also upregulation of BDNF production in the brain in animal models of depression.^[15] These antidepressant effects have been linked to endogenous opioid peptides acting at δ- and μ-opioid receptors,^[16] and so can also be produced by enkephalinase inhibitors such as RB-101.^[17] ] However, in human models the data for antidepressant effects remains inconclusive. In the 2008 Phase 2 clinical trial by Astra Zeneca, NCT00759395, 15 patients were treated with the selective delta agonist AZD 2327. The results showed no significant effect on mood suggesting that δ-opioid receptor modulation might not participate in the regulation of mood in humans. However, doses were administered at low doses and the pharmacological data also remains inconclusive.^[18][19] Further trials are required.

Another interesting aspect of δ-opioid receptor function is the suggestion of μ/δ-opioid receptor interactions. At the extremes of this suggestion lies the possibility of a μ/δ opioid receptor oligomer. The evidence for this stems from the different binding profiles of typical mu and delta agonists such as morphine and DAMGO respectively, in cells that coexpress both receptors compared to those in cells that express them individually. In addition, work by Fan and coworkers shows the restoration of the binding profiles when distal carboxyl termini are truncated at either receptor, suggesting that the termini play a role in the oligomerization.^[20] While this is exciting, rebuttal by the Javitch and coworkers suggest the idea of oligomerization may be overplayed. Relying on RET, Javitch and coworkers showed that RET signals were more characteristic of random proximity between receptors, rather than an actual bond formation between receptors, suggesting that discrepancies in binding profiles may be the result of downstream interactions, rather than novel effects due to oligomerization.^[21] Nevertheless, coexpression of receptors remains unique and potentially useful in the treatment of mood disorders and pain.

Recent work indicates that exogenous ligands that activate the delta receptors mimic the phenomenon known as ischemic preconditioning.^[22] Experimentally, if short periods of transient ischemia are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then affected. Opiates and opioids with DOR activity mimic this effect. In the rat model, introduction of DOR ligands results in significant cardioprotection.^[23]

Ligands

Until comparatively recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors for which selective ligands have long been available.

However, there are now several selective δ-opioid receptor agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80,^[24] the more potent (+)-BW373U86,^[25] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,^[26] and the mixed μ/δ agonist DPI-3290, which is a much more potent analgesic than the more highly selective δ agonists.^[27] Selective antagonists for the δ receptor are also available, with the best known being the opiate derivative naltrindole.^[28]

 

Agonists

 

A showing of selective delta opioid ligands. Blue represents a common phenolic moiety, yellow a basic nitrogen, and red a diethyl amide moiety which is not set in stone, but rather a bulky region that fits into a hydrophobic pocket.

Peptides

• Leu-enkephalin
• Met-enkephalin
• Deltorphins
• DADLE
• DPDPE

Non-peptides

• ADL-5859^[29]
• BU-48
• BW373U86
• DPI-221
• DPI-287
• DPI-3290
• RWJ-394674-
• SNC-80
• TAN-67
• Amoxapine (partial agonist)^[30]
• Cannabidiol (allosteric modulator, non-selective)^[31]
• Desmethylclozapine
• Mitragynine
• Mitragynine pseudoindoxyl
• Norbuprenorphine (peripherally restricted)
• N-Phenethyl-14-ethoxymetopon
• 7-Spiroindanyloxymorphone
• Tetrahydrocannabinol (allosteric modulator, non-selective)^[31]
• Xorphanol

Antagonists

• Buprenorphine
• Naltriben
• Naltrindole
• Mitragynine
• 7-Hydroxymitragynine

Interactions

δ-opioid receptors have been shown to interact with β₂ adrenergic receptors,^[32] arrestin β₁^[33] and GPRASP1.^[34]

See also

• κ-opioid receptor
• μ-opioid receptor

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000050511 - Ensembl, May 2017
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Further reading

• Narita M, Funada M, Suzuki T (Jan 2001). "Regulations of opioid dependence by opioid receptor types". Pharmacology & Therapeutics. 89 (1): 1–15. doi:10.1016/S0163-7258(00)00099-1. PMID 11316510.
• Evans CJ, Keith DE, Morrison H, Magendzo K, Edwards RH (Dec 1992). "Cloning of a delta opioid receptor by functional expression". Science. 258 (5090): 1952–5. Bibcode:1992Sci...258.1952E. doi:10.1126/science.1335167. PMID 1335167.
• Offermanns S, Schultz G, Rosenthal W (Feb 1991). "Evidence for opioid receptor-mediated activation of the G-proteins, Go and Gi2, in membranes of neuroblastoma x glioma (NG108-15) hybrid cells". The Journal of Biological Chemistry. 266 (6): 3365–8. doi:10.1016/S0021-9258(19)67799-9. PMID 1671672.
• Simonin F, Befort K, Gavériaux-Ruff C, Matthes H, Nappey V, Lannes B, Micheletti G, Kieffer B (Dec 1994). "The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain". Molecular Pharmacology. 46 (6): 1015–21. PMID 7808419.
• Befort K, Mattéi MG, Roeckel N, Kieffer B (Mar 1994). "Chromosomal localization of the delta opioid receptor gene to human 1p34.3-p36.1 and mouse 4D bands by in situ hybridization". Genomics. 20 (1): 143–5. doi:10.1006/geno.1994.1146. PMID 8020949.
• Knapp RJ, Malatynska E, Fang L, Li X, Babin E, Nguyen M, Santoro G, Varga EV, Hruby VJ, Roeske WR (1994). "Identification of a human delta opioid receptor: cloning and expression". Life Sciences. 54 (25): PL463-9. doi:10.1016/0024-3205(94)90138-4. PMID 8201839.
• Georgoussi Z, Carr C, Milligan G (Jul 1993). "Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go". Molecular Pharmacology. 44 (1): 62–9. PMID 8393523.
• Bzdega T, Chin H, Kim H, Jung HH, Kozak CA, Klee WA (Oct 1993). "Regional expression and chromosomal localization of the delta opiate receptor gene". Proceedings of the National Academy of Sciences of the United States of America. 90 (20): 9305–9. Bibcode:1993PNAS...90.9305B. doi:10.1073/pnas.90.20.9305. PMC 47556. PMID 8415697.
• Ho MK, Wong YH (Jun 1997). "Functional role of amino-terminal serine16 and serine27 of G alphaZ in receptor and effector coupling". Journal of Neurochemistry. 68 (6): 2514–22. doi:10.1046/j.1471-4159.1997.68062514.x. PMID 9166747. S2CID 24703413.
• Hedin KE, Bell MP, Kalli KR, Huntoon CJ, Sharp BM, McKean DJ (Dec 1997). "Delta-opioid receptors expressed by Jurkat T cells enhance IL-2 secretion by increasing AP-1 complexes and activity of the NF-AT/AP-1-binding promoter element". Journal of Immunology. 159 (11): 5431–40. PMID 9548483.
• Jordan BA, Devi LA (Jun 1999). "G-protein-coupled receptor heterodimerization modulates receptor function". Nature. 399 (6737): 697–700. Bibcode:1999Natur.399..697J. doi:10.1038/21441. PMC 3125690. PMID 10385123.
• Petaja-Repo UE, Hogue M, Laperriere A, Walker P, Bouvier M (May 2000). "Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor". The Journal of Biological Chemistry. 275 (18): 13727–36. doi:10.1074/jbc.275.18.13727. PMID 10788493. S2CID 8293320.
• Gelernter J, Kranzler HR (Jul 2000). "Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence". Human Genetics. 107 (1): 86–8. doi:10.1007/s004390050016. PMID 10982041.
• Guo J, Wu Y, Zhang W, Zhao J, Devi LA, Pei G, Ma L (Nov 2000). "Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation". Molecular Pharmacology. 58 (5): 1050–6. doi:10.1124/mol.58.5.1050. PMID 11040053.
• Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (Nov 2000). "Heterodimerization of mu and delta opioid receptors: A role in opiate synergy". The Journal of Neuroscience. 20 (22): RC110. doi:10.1523/JNEUROSCI.20-22-j0007.2000. PMC 3125672. PMID 11069979.
• Xu W, Chen C, Huang P, Li J, de Riel JK, Javitch JA, Liu-Chen LY (Nov 2000). "The conserved cysteine 7.38 residue is differentially accessible in the binding-site crevices of the mu, delta, and kappa opioid receptors". Biochemistry. 39 (45): 13904–15. doi:10.1021/bi001099p. PMID 11076532.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Saeed RW, Stefano GB, Murga JD, Short TW, Qi F, Bilfinger TV, Magazine HI (Dec 2000). "Expression of functional delta opioid receptors in vascular smooth muscle". International Journal of Molecular Medicine. 6 (6): 673–7. doi:10.3892/ijmm.6.6.673. PMID 11078827.
• Xiang B, Yu GH, Guo J, Chen L, Hu W, Pei G, Ma L (Feb 2001). "Heterologous activation of protein kinase C stimulates phosphorylation of delta-opioid receptor at serine 344, resulting in beta-arrestin- and clathrin-mediated receptor internalization". The Journal of Biological Chemistry. 276 (7): 4709–16. doi:10.1074/jbc.M006187200. PMID 11085981. S2CID 84945988.
• Yeo A, Samways DS, Fowler CE, Gunn-Moore F, Henderson G (Mar 2001). "Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells". Journal of Neurochemistry. 76 (6): 1688–700. doi:10.1046/j.1471-4159.2001.00185.x. PMID 11259487. S2CID 2755275.

External links

• "Opioid Receptors: δ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• delta+Opioid+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)