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δ receptor

Family: Opioid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 372 1p36.1-p34.3 OPRD1 opioid receptor, delta 1 29,53
Mouse 7 372 4 D1-D3 Oprd1 opioid receptor, delta 1 15,27,61
Rat 7 372 5q36 Oprd1 opioid receptor, delta 1 1
Previous and Unofficial Names
DOR
DOR-1
OP1
delta
Delta opiod receptor
DOP
D-OR-1
Opioid receptor delta 1
delta-type opioid receptor
opioid receptor A
opioid receptor, delta 1
Nbor
mDOR
DOP-r
Database Links
ChEMBL Target 136 (Hs), 10315 (Mm), 10526 (Rn)
DrugBank Target 467 (Hs)
Ensembl ENSG00000116329 (Hs), ENSMUSG00000050511 (Mm), ENSRNOG00000010531 (Rn)
Entrez Gene 4985 (Hs), 18386 (Mm), 24613 (Rn)
GeneCards OPRD1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Oprd1 (Mm)
HomoloGene 20252 (Hs)
Human Protein Reference Database 01308 (Hs)
InterPro P41143 (Hs), P32300 (Mm), P33533 (Rn)
KEGG Gene hsa:4985 (Hs), mmu:18386 (Mm), rno:24613 (Rn)
OMIM 165195 (Hs)
PhosphoSitePlus P41143 (Hs), P32300 (Mm), P33533 (Rn)
Protein Ontology (PRO) PRO:000001579 (Hs)
RefSeq Nucleotide NM_000911 (Hs), NM_013622 (Mm), NM_012617 (Rn)
RefSeq Protein NP_000902 (Hs), NP_038650 (Mm), NP_036749 (Rn)
TreeFam ENSG00000116329 (Hs), ENSMUSG00000050511 (Mm), ENSRNOG00000010531 (Rn)
UniGene Hs. 372 (Hs)
UniProt P41143 (Hs), P32300 (Mm), P33533 (Rn)
Wikipedia δ receptor
Opioid receptors
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the delta opioid receptor bound to naltrindole
PDB Id:  4EJ4
Ligand:  naltrindole
Resolution:  3.4Å
Species:  Mouse
References: 
Search for other structures on the PDB
Search by keyword: Opioid receptors δ receptor Search by accession number: P33533, P41143, P32300
Natural/Endogenous Ligand(s)
β-endorphin {Sp: Human} , β-endorphin {Sp: Rat} , β-endorphin {Sp: Mouse}
dynorphin A {Sp: Human, Mouse, Rat}
dynorphin A-(1-13) {Sp: Human, Mouse, Rat}
dynorphin A-(1-8) {Sp: Human, Mouse, Rat}
dynorphin B {Sp: Human, Mouse, Rat}
endomorphin-1 {Sp: Human}
[Leu]enkephalin {Sp: Human, Mouse, Rat}
[Met]enkephalin {Sp: Human, Mouse, Rat}
Rank order of potency (Human)
β-endorphin = [Leu]enkephalin = [Met]enkephalin > dynorphin A
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[D-Ala2]deltorphin I Hs Agonist 9.35 pKd 12,56
diprenorphine Hs Full agonist 9.3 pKi 58
DSLET Hs Full agonist 9.3 pKi 58
[3H]diprenorphine Hs Full agonist 9.3 pKi 58
DADLE Hs Full agonist 9.2 pKi 58
(-)-cyclazocine Hs Partial agonist 9.1 pKi 58
DADLE Mm Full agonist 9.1 pKi 47
β-endorphin {Sp: Human} Mm Full agonist 9.0 pKi 47
(-)-bremazocine Hs Full agonist 9.0 pKi 58
deltorphin II Hs Full agonist 8.8 pKi 58
DPDPE Hs Full agonist 8.8 pKi 39,58
etorphine Hs Full agonist 8.8 pKi 58
[Leu]enkephalin {Sp: Human, Mouse, Rat} Hs Full agonist 8.7 pKi 58
DSTBULET Hs Full agonist 8.6 pKi 11
deltorphin II Mm Full agonist 8.5 pKi 47
(-)-EKC Hs Full agonist 8.5 pKi 58
dynorphin A-(1-8) {Sp: Human, Mouse, Rat} Hs Partial agonist 8.4 pKi 58
[Leu]enkephalin {Sp: Human, Mouse, Rat} Mm Full agonist 8.4 pKi 47
β-endorphin {Sp: Human} Hs Full agonist 8.3 pKi 58
DSLET Mm Full agonist 8.3 pKi 47
nalmefene Hs Partial agonist 8.1 pKi 58
dynorphin-(1-11) Hs Full agonist 8.0 pKi 58
DPDPE Mm Full agonist 7.9 pKi 47
dynorphin A-(1-13) {Sp: Human, Mouse, Rat} Hs Full agonist 7.8 pKi 58
dynorphin B {Sp: Human, Mouse, Rat} Hs Full agonist 7.8 pKi 58
dynorphin A {Sp: Human, Mouse, Rat} Hs Full agonist 7.4 pKi 58
nalorphine Hs Partial agonist 7.4 pKi 58
(-)-pentazocine Hs Full agonist 7.3 pKi 58
SNC80 Hs Full agonist 7.2 pKi 4,46
normorphine Hs Full agonist 7.1 pKi 58
(-)-methadone Hs Full agonist 6.9 pKi 58
morphine Hs Full agonist 6.9 pKi 58
fentanyl Hs Full agonist 6.8 pKi 58
dihydromorphine Hs Full agonist 6.7 pKi 58
etonitazene Hs Full agonist 6.7 pKi 58
endomorphin-1 {Sp: Human} Hs Full agonist 6.1 pKi 20
[D-Ala2]deltorphin II Hs Full agonist 5.6 pKi 13
α-neoendorphin {Sp: Human, Mouse, Rat} Mm Full agonist 8.0 pIC50 61
[Met]enkephalin {Sp: Human, Mouse, Rat} Mm Full agonist 7.4 pIC50 61
EKC Mm Full agonist 6.2 pIC50 61
View species-specific agonist tables
Agonist Comments
The above reported affinities are based on binding to receptors in membrane preparations with buffers optimized for agonist binding. The affinity of agonists in intact cells, or in the presence of sodium and GTP/GDP analogues is often different and multiple affinity sites have been observed [30].

Discrimination of full or partial agonism is very dependent on the level of receptor expression and on the assay used to monitor agonist effects. Many agents may behave as full agonists or potent partial agonists in cell lines expressing cloned receptors in high concentration, but in other environments they may show only weak agonist activity. The identification of agonist activity in the table is largely based on the ability to stimulate GTPγ35S binding in cell lines expressing cloned human δ receptors. Agents giving 85% or greater stimulation than that given by DPDPE have been characterized as Full Agonists [58].

Diprenorphine is a very weak partial agonist and in some assays may behave as an antagonist.

Deltorphin II is endogenous in some species of amphibians.

Alternative sources for binding information for the same ligands in different species can be found in the following reference [42].

Although many of the agonists are considered to be highly selective for the δ opioid receptor, data using δ and μ knockout mice show that ICV administration of opioids considered δ receptor selective, such as deltorphin and DPDPE can activate μ opioid receptors to elicit analgesia [50].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
naltriben Mm Antagonist 10.9 pKi 47
naltrindole Mm Antagonist 10.7 pKi 47
naltriben Hs Antagonist 10.0 pKi 55,58
naltriben Rn Inverse agonist 10.0 pKi 40
naltrindole Hs Antagonist 9.7 pKi 45,58
BNTX Mm Antagonist 9.2 pKi 47
TIPPψ Hs Inverse agonist 9.0 pKi 58
(-)-quadazocine Hs Antagonist 8.9 pKi 58
BNTX Rn Inverse agonist 8.7 pKi 40
BNTX Hs Antagonist 8.4 pKi 58
nor-binaltorphimine Hs Antagonist 8.2 pKi 58
naltrexone Hs Antagonist 8.0 pKi 58
β-FNA Hs Antagonist 7.9 pKi 58
naloxone Mm Antagonist 7.8 pKi 47
ICI 174,864 Rn Inverse agonist 7.4 pKi 40
naloxone Hs Antagonist 7.2 pKi 58
naloxone Hs Antagonist 7.2 pKi 58
naltrexone Mm Antagonist 6.8 pKi 47
CTAP Hs Antagonist 6.4 pKi 58
nor-binaltorphimine Mm Antagonist 6.7 pIC50 61
naloxone Mm Antagonist 6.2 pIC50 61
View species-specific antagonist tables
Antagonist Comments
δ opioid receptors were one of the first G protein-coupled receptors to be shown to exhibit constitutive activity [10]. As observed with agonist binding affinities, some antagonist affinities can be modulated markedly by ions and GTP/GDP analogues [40]. The assigning of an antagonist as an inverse agonist or neutral antagonist appears to be dependent upon the state of the receptor, and following agonist treatment many neutral antagonists and weak partial agonists have been reported to become inverse agonists [32].
Allosteric Regulator Comments
Although no small molecules are considered direct allosteric regulators of the δ opioid receptor, a number of proteins such as G protein-coupled receptor kinases, β-arrestins and G proteins clearly regulate receptor affinities and function. Furthermore, sodium and guanyl nucleotides can modify the functional δ opioid receptor complex and G protein interaction. Also, other G protein-coupled receptors appear to be able to form heterodimers with δ opioid receptors potentially modifying δ opioid activity [48] reviewed in [8,14].

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Phospholipase C stimulation
Potassium channel
Calcium channel
Other - See Comments
Comments:  δ receptors have been shown to modulate many kinase cascades including ERKs, Akts, JNKs, STAT3, P38 involving Src, Ras, Rac, Raf-1, Cdc42, RTKs.
References:  26,31,33,51
Tissue Distribution
Immune cells.
Species:  Human
Technique:  RT-PCR.
References:  19
Skin.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  49
CNS: cortex, olfactory bulb, olfactory tubercle, caudate putamen, nucleus accumbens, amygdala.
Species:  Mouse
Technique:  Radioligand binding.
References:  21,28
Embryo:
CNS: medial habenula, hypothalamus, pons, medulla, dorsal root ganglion, caudate putamen, medial habenula, tegmentum, trigeminal nucleus.
Periphery: heart, limb bud, tooth, olfactory epithelium.
Species:  Mouse
Technique:  in situ hybridisation.
References:  64
Intestine.
Species:  Mouse
Technique:  RT-PCR.
References:  44
Pregnant uterus and placenta.
Species:  Mouse
Technique:  in situ hybridisation.
References:  63
CNS: superficial layers (laminae I and II) of the dorsal horn of the spinal cord.
Species:  Rat
Technique:  Radioligand binding.
References:  2
Ear: cochlea.
Species:  Rat
Technique:  RT-PCR and immunocytochemistry.
References:  25
Autoradiographic binding with [3H]DPDPE and [3H]DSLET, in an attempt to demonstrate differential distribution of DOP subtypes, showed no major differences in receptor distribution although regional differences in binding levels between the two δ ligands were observed.
Brain: dorsomedial hypothalamus, ventromedial hypothalamus, superior colliculis, medial division of bed nucleus stria terminalis, external cortex of the inferior colliculis, amygdaloid nuclei, cingulate cortex, CA1, CA2, and CA3 regions of Ammon's horn, dentate gyrus, laminar VI of the frontal, forelimb, hindlimb and parietal cortices, nucleus accumbens, caudate/putamen.
Species:  Rat
Technique:  Radioligand binding.
References:  23
Widely distributed throughout the CNS, most prominant expression in the forebrain regions.
Caudate putamen, nucleus accumbens, amygdala, pontine nucleus, olfactory bulb, olfactory tubercle > interpeduncular nucleus, cortex (most dense in layers II-III and V-VI) > thalamus, hypothalamus, stria terminalis, hippocampus, globus pallidus, preoptic area, colliculi.
Virtually no binding in the periaqueductal grey and raphe nuclei.
Species:  Rat
Technique:  Radioligand binding.
References:  5,36
Tissue Distribution Comments
Studies of the distribution of δ opioid receptors in humans has been limited to autoradiography and in situ hybridisation analysis [5,43].
DOP receptors in the CNS appear to have a similar distribution in rat and human [5] and mouse [21]. One notable exception is the spinal cord where DOP receptors are considerably more abundant in the dorsal horn and dorsal root ganglia than in rodent counterparts [38].
Many brain stem nuclei (such as the lateral reticular nucleus, the medial vestibular nucleus and trapezoid nucleus) express high levels of DOP mRNA yet DOP binding is undetectable [65].
For a review of δ opioid receptor expression in the rat see [35].
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of musculature contraction of sections of mouse vas deferens following stimulation of the intramural nerves.
Species:  Mouse
Tissue:  Vas deferens.
Response measured:  Inhibition of electrically-evoked contraction.
References:  24
Measurement of musculature contraction of sections of mouse ileum following stimulation of the intramural nerves.
Species:  Mouse
Tissue:  Ileum.
Response measured:  Inhibition of electrically-evoked contraction.
References:  54
Measurement of cAMP levels in NG108-15 cells (a fusion of a mouse neuroblastoma, the genetic source of δ receptors, and a rat glioma cell line).
Species:  Mouse
Tissue:  NG108-15 cell line.
Response measured:  Inhibition of cAMP accumulation.
References:  52
Measurement of [35S]GTPγS binding in NG108-15 cells (a fusion of a mouse neuroblastoma, the genetic source of δ receptors, and a rat glioma cell line).
Species:  Mouse
Tissue:  NG108-15 cell line.
Response measured:  [35S]GTPγS binding.
References:  57
Physiological Functions
Spinal analgesia in the mouse. Intrathecal injections of δ opioid agonists induce analgesia but require externalisation of δ receptors via interaction with products from the substance P precursor.
Species:  Mouse
Tissue:  Periaqueductal gray neuronal slices.
References:  22
In vivo δ receptor coupling to ion channels is not a robust phenomenon in some areas of the CNS unless the system is triggered by externalisation.
Species:  Mouse
Tissue: 
References:  22
GABAergic inhibition via δ receptors acting on locus coeruleus and hippocampal neurones has been inferred by measurement of the frequency of miniture inhibitory postsynaptic currents (IPSCs).
Species:  Rat
Tissue:  Brain slices.
References:  34,41
Reversal of thermal hyperalgesic activity by delta opioid agonists in a chronic inflammation model.
Species:  Rat
Tissue:  In vivo.
References:  7,17
Seizure promoting activity of δ receptor agonists administered systemically.
Species:  Mouse
Tissue:  In vivo.
References:  6
Physiological Functions Comments
For reviews on the signalling and function of the δ opioid receptor see [9,31,60]
Physiological Consequences of Altering Gene Expression
Homozygote δ opioid receptor knockout mice are viable, fertile and show no gross anatomical deficits.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16,65
δ opioid receptor knockout mice exhibit increased anxiety and depressive-like behaviour.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16
δ opioid receptor knockout mice exhibit increased sensitivity to inflammatory pain.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  37
δ opioid receptor knockout mice exhibit modified morphine tolerance.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  65
Physiological Consequences of Altering Gene Expression Comments
Some of the physiological effects observed with knockout mice may be mouse-strain restricted and not generalise to all backgrounds.
For a review on opioid receptor knockout mice see reference [18].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Oprd1tm1Jep Oprd1tm1Jep/Oprd1tm1Jep
involves: 129S/SvEv * C57BL/6J		 MGI:97438  MP:0009748 abnormal behavioral response to addictive substance PMID: 12486185 
Oprd1tm1Jep Oprd1tm1Jep/Oprd1tm1Jep
involves: 129S/SvEv * C57BL/6J		 MGI:97438  MP:0001980 abnormal chemically-elicited antinociception PMID: 12486185 
Oprd1tm1Jep|Oprm1tm1Jep Oprd1tm1Jep/Oprd1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep
involves: 129S/SvEv * 129S2/SvPas		 MGI:97438  MGI:97441  MP:0008872 abnormal physiological response to xenobiotic PMID: 17544222 
Oprd1tm1Kff Oprd1tm1Kff/Oprd1tm1Kff
involves: 129/Sv * C57BL/6		 MGI:97438  MP:0003064 decreased coping response PMID: 10835636 
Oprd1tm1Kff Oprd1tm1Kff/Oprd1tm1Kff
involves: 129/Sv * C57BL/6		 MGI:97438  MP:0001399 hyperactivity PMID: 10835636 
Oprd1tm1Jep|Oprm1tm1Jep Oprd1tm1Jep/Oprd1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep
involves: 129S/SvEv * 129S2/SvPas		 MGI:97438  MGI:97441  MP:0009778 impaired behavioral response to anesthetic PMID: 17544222 
Oprd1tm1Jep|Oprm1tm1Jep Oprd1tm1Jep/Oprd1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep,Oprm1tm1Jep/Oprm1tm1Jep
involves: 129S/SvEv * 129S2/SvPas		 MGI:97438  MGI:97441  MP:0009757 impaired behavioral response to morphine PMID: 17544222 
Oprd1tm1Kff Oprd1tm1Kff/Oprd1tm1Kff
involves: 129/Sv * C57BL/6		 MGI:97438  MP:0001363 increased anxiety-related response PMID: 10835636 
Oprd1tm1Dgen Oprd1tm1Dgen/Oprd1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:97438  MP:0002906 increased susceptibility to pharmacologically induced seizures
Biologically Significant Variant Comments
δ1 and δ2 receptor subtypes have been proposed based upon in vivo pharmacology of DPDPE and deltorphin II. However, no δ opioid receptor variants have been characterised as δ1 and δ2 receptor proteins, and knockout of the δ receptor gene in mice eliminates binding of the two ligands. There is mounting evidence that hetero-oligomerisation of the δ and κ opioid receptors results in the δ1 subtype and that κ/δ hetero-oligomers are functional in the spinal cord [3,16,59,62].
δ receptors have also been proposed to interact with μ receptors (for review see [62]). The observed pharmacological cross-talk may partially arise from agonist cross-reactivity. In vivo and knockout data suggest that analgesia from ICV administration of DPDPE or deltorphan II can occur via μ opioid receptors [50].
Pharmacological diversity of δ receptors likely results from interaction with different proteins (such as the formation of heterooligomers with other GPCRs) or differential posttranslational modifications as opposed to distinct variants of the primary sequence of the receptor protein [14].

REFERENCES

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To cite this database page, please use the following:

Anna Borsodi, Girolamo Caló, Charles Chavkin, MacDonald J. Christie, Olivier Civelli, Brian M. Cox, Lakshmi A. Devi, Christopher Evans, Graeme Henderson, Volker Höllt, Brigitte Kieffer, Ian Kitchen, Mary-Jeanne Kreek, Lee-Yuan Liu-Chen, Jean-Claude Meunier, Philip S. Portoghese, Toni S. Shippenberg, Eric J. Simon, Lawrence Toll, John R. Traynor, Hiroshi Ueda, Yung H. Wong.
Opioid receptors: δ receptor. Last modified on 13/03/2013. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=317.


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