delta Opioid receptor

Opioid receptor, delta 1
Rendering based on PDB 1OZC.
Available structures PDB 1OZC, 2IQM
Identifiers
Symbols	OPRD1; OPRD
External IDs	OMIM: 165195 MGI: 97438 HomoloGene: 20252 IUPHAR: δ GeneCards: OPRD1 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • delta-opioid receptor activity • protein binding Cellular component • membrane fraction • cytoplasm • plasma membrane • plasma membrane • integral to plasma membrane • vesicle • dendrite membrane • axon terminus • membrane raft • postsynaptic membrane Biological process • protein import into nucleus, translocation • immune response • G-protein coupled receptor protein signaling pathway • G-protein signaling, coupled to cyclic nucleotide second messenger • inhibition of adenylate cyclase activity by G-protein signaling pathway • neuropeptide signaling pathway • adult locomotory behavior • negative regulation of calcium ion transport via voltage-gated calcium channel activity • regulation of sensory perception of pain • cellular response to growth factor stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4985	18386
Ensembl	ENSG00000116329	ENSMUSG00000050511
UniProt	P41143	P32300
RefSeq (mRNA)	NM_000911.3	NM_013622.3
RefSeq (protein)	NP_000902.3	NP_038650.3
Location (UCSC)	Chr 1: 29.14 – 29.19 Mb	Chr 4: 131.67 – 131.7 Mb
PubMed search	[1]	[2]

The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.^[1]

Function

Activation of delta receptors produces some analgesia, although less than that of mu-opioid agonists.^[2] Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.^[3]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep,^[4] 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.^[5] 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 mu-opioid agonist alfentanil, without affecting pain relief.^[6] It thus seems likely that while delta 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 mu agonists currently used for pain relief.

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^[7] and also upregulation of BDNF production in the brain in animal models of depression.^[8] These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors,^[9] and so can also be produced by enkephalinase inhibitors such as RB-101.^[10]

Recent work indicates that exogenous ligands that activate the delta receptors mimic the phenomenon known as ischemic preconditioning.^[11] 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 effected. Opiates and opioids with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection.^[12]

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 delta opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80,^[13] the more potent (+)-BW373U86,^[14] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,^[15] and the mixed mu/delta agonist DPI-3290, which is a much more potent analgesic than the more highly selective delta agonists.^[16] Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole.^[17]

Agonists

Peptides

• Leu-enkephalin
• Met-enkephalin
• Deltorphins

Non-peptides

• 7-Spiroindanyloxymorphone
• N-Phenethyl-14-ethoxymetopon
• ADL-5859^[18]
• BU-48
• SNC-80
• BW373U86
• DPI-221
• DPI-287
• DPI-3290
• TAN-67
• RWJ-394,674
• Norbuprenorphine

Mitragyna Speciosa(aka Kratom) Indole Agonists:

• Mitragynine
• Mitragynine-pseudoindoxyl

Antagonists

• Naltriben
• Naltrindole

Interactions

Delta opioid receptors have been shown to interact with beta-2 adrenergic receptors,^[19] arrestin beta 1^[20] and GPRASP1.^[21]

References

1. ^ Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, Slate CA, Ehlert FJ, Roeske WR, Yamamura HI (1999). "The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy". Pharmacol. Rev. 51 (3): 503–32. PMID 10471416. http://pharmrev.aspetjournals.org/content/51/3/503.full. 
2. ^ Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (2004). "Agonist-specific regulation of the delta-opioid receptor". Life Sci. 76 (6): 599–612. doi:10.1016/j.lfs.2004.07.020. PMID 15567186. 
3. ^ Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (2006). "The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol". J. Pharmacol. Exp. Ther. 317 (3): 1337–48. doi:10.1124/jpet.105.095810. PMID 16537798. 
4. ^ Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, Szeto HH (1998). "Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep". Am. J. Obstet. Gynecol. 178 (2): 397–401. doi:10.1016/S0002-9378(98)80032-X. PMID 9500506. http://www.ajog.org/article/S0002-9378(98)80032-X/pdf. 
5. ^ Gallantine EL, Meert TF (2005). "A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80". Basic Clin. Pharmacol. Toxicol. 97 (1): 39–51. doi:10.1111/j.1742-7843.2005.pto_07.x. PMID 15943758. 
6. ^ Su YF, McNutt RW, Chang KJ (1998). "Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception". J. Pharmacol. Exp. Ther. 287 (3): 815–23. PMID 9864259. http://jpet.aspetjournals.org/cgi/content/abstract/287/3/815. 
7. ^ Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH (2002). "Behavioral effects of delta-opioid receptor agonists: potential antidepressants?". Jpn. J. Pharmacol. 90 (1): 1–6. doi:10.1254/jjp.90.1. PMID 12396021. 
8. ^ Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH (2006). "Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats". Brain Res. 1069 (1): 172–81. doi:10.1016/j.brainres.2005.11.005. PMC 1780167. PMID 16364263. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1780167. 
9. ^ Zhang H, Torregrossa MM, Jutkiewicz EM, Shi YG, Rice KC, Woods JH, Watson SJ, Ko MC (2006). "Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects". Eur. J. Neurosci. 23 (4): 984–94. doi:10.1111/j.1460-9568.2006.04621.x. PMC 1462954. PMID 16519663. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1462954. 
10. ^ Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH (2006). "Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects". Eur. J. Pharmacol. 531 (1-3): 151–9. doi:10.1016/j.ejphar.2005.12.002. PMC 1828120. PMID 16442521. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1828120. 
11. ^ Zhang J, Qian H, Zhao P, Hong SS, Xia Y (2006). "Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor". Stroke 37 (4): 1094–9. doi:10.1161/01.STR.0000206444.29930.18. PMID 16514101. 
12. ^ Guo L, Zhang L, Zhang DC (2005). "[Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications]" (in Chinese). Sheng li ke xue jin zhan [Progress in physiology] 36 (4): 333–6. PMID 16408774. 
13. ^ Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC (1994). "Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist". J. Med. Chem. 37 (14): 2125–8. doi:10.1021/jm00040a002. PMID 8035418. 
14. ^ Calderon SN, Rice KC, Rothman RB, Porreca F, Flippen-Anderson JL, Kayakiri H, Xu H, Becketts K, Smith LE, Bilsky EJ, Davis P, Horvath R (1997). "Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands". J. Med. Chem. 40 (5): 695–704. doi:10.1021/jm960319n. PMID 9057856. 
15. ^ Jutkiewicz EM (2006). "The antidepressant -like effects of delta-opioid receptor agonists". Mol. Interv. 6 (3): 162–9. doi:10.1124/mi.6.3.7. PMID 16809477. 
16. ^ Ananthan S (2006). "Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics". AAPS J 8 (1): E118–25. doi:10.1208/aapsj080114. PMC 2751430. PMID 16584118. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2751430. 
17. ^ Portoghese PS, Sultana M, Takemori AE (1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". Eur. J. Pharmacol. 146 (1): 185–6. doi:10.1016/0014-2999(88)90502-X. PMID 2832195. 
18. ^ Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (October 2008). "Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)". Journal of Medicinal Chemistry 51 (19): 5893–6. doi:10.1021/jm8008986. PMID 18788723. 
19. ^ McVey, M; Ramsay D, Kellett E, Rees S, Wilson S, Pope A J, Milligan G (Apr. 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". J. Biol. Chem. (United States) 276 (17): 14092–9. doi:10.1074/jbc.M008902200. ISSN 0021-9258. PMID 11278447. 
20. ^ Cen, B; Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G (Mar. 2001). "Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor". J. Neurochem. (United States) 76 (6): 1887–94. doi:10.1046/j.1471-4159.2001.00204.x. ISSN 0022-3042. PMID 11259507. 
21. ^ Whistler, Jennifer L; Enquist Johan, Marley Aaron, Fong Jamie, Gladher Fredrik, Tsuruda Pamela, Murray Stephen R, Von Zastrow Mark (Jul. 2002). "Modulation of postendocytic sorting of G protein-coupled receptors". Science (United States) 297 (5581): 615–20. doi:10.1126/science.1073308. PMID 12142540. 

Further reading

• Narita M, Funada M, Suzuki T (2001). "Regulations of opioid dependence by opioid receptor types.". Pharmacol. Ther. 89 (1): 1–15. doi:10.1016/S0163-7258(00)00099-1. PMID 11316510. 
• Evans CJ, Keith DE, Morrison H, et al. (1993). "Cloning of a delta opioid receptor by functional expression.". Science 258 (5090): 1952–5. doi:10.1126/science.1335167. PMID 1335167. 
• Offermanns S, Schultz G, Rosenthal W (1991). "Evidence for opioid receptor-mediated activation of the G-proteins, Go and Gi2, in membranes of neuroblastoma x glioma (NG108-15) hybrid cells.". J. Biol. Chem. 266 (6): 3365–8. PMID 1671672. 
• Simonin F, Befort K, Gavériaux-Ruff C, et al. (1995). "The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain.". Mol. Pharmacol. 46 (6): 1015–21. PMID 7808419. 
• Befort K, Mattéi MG, Roeckel N, Kieffer B (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, et al. (1994). "Identification of a human delta opioid receptor: cloning and expression.". Life Sci. 54 (25): PL463–9. doi:10.1016/0024-3205(94)90138-4. PMID 8201839. 
• Georgoussi Z, Carr C, Milligan G (1993). "Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go.". Mol. Pharmacol. 44 (1): 62–9. PMID 8393523. 
• Bzdega T, Chin H, Kim H, et al. (1993). "Regional expression and chromosomal localization of the delta opiate receptor gene.". Proc. Natl. Acad. Sci. U.S.A. 90 (20): 9305–9. doi:10.1073/pnas.90.20.9305. PMC 47556. PMID 8415697. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=47556. 
• Ho MK, Wong YH (1997). "Functional role of amino-terminal serine16 and serine27 of G alphaZ in receptor and effector coupling.". J. Neurochem. 68 (6): 2514–22. doi:10.1046/j.1471-4159.1997.68062514.x. PMID 9166747. 
• Hedin KE, Bell MP, Kalli KR, et al. (1998). "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.". J. Immunol. 159 (11): 5431–40. PMID 9548483. 
• Jordan BA, Devi LA (1999). "G-protein-coupled receptor heterodimerization modulates receptor function.". Nature 399 (6737): 697–700. doi:10.1038/21441. PMC 3125690. PMID 10385123. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3125690. 
• Petaja-Repo UE, Hogue M, Laperriere A, et al. (2000). "Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor.". J. Biol. Chem. 275 (18): 13727–36. doi:10.1074/jbc.275.18.13727. PMID 10788493. 
• Gelernter J, Kranzler HR (2000). "Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence.". Hum. Genet. 107 (1): 86–8. doi:10.1007/s004390050016. PMID 10982041. 
• Guo J, Wu Y, Zhang W, et al. (2000). "Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation.". Mol. Pharmacol. 58 (5): 1050–6. PMID 11040053. 
• Gomes I, Jordan BA, Gupta A, et al. (2001). "Heterodimerization of mu and delta opioid receptors: A role in opiate synergy.". J. Neurosci. 20 (22): RC110. PMID 11069979. 
• Xu W, Chen C, Huang P, et al. (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 (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948. 
• Saeed RW, Stefano GB, Murga JD, et al. (2001). "Expression of functional delta opioid receptors in vascular smooth muscle.". Int. J. Mol. Med. 6 (6): 673–7. PMID 11078827. 
• Xiang B, Yu GH, Guo J, et al. (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.". J. Biol. Chem. 276 (7): 4709–16. doi:10.1074/jbc.M006187200. PMID 11085981. 
• Yeo A, Samways DS, Fowler CE, et al. (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.". J. Neurochem. 76 (6): 1688–700. doi:10.1046/j.1471-4159.2001.00185.x. PMID 11259487. 

External links

• "Opioid Receptors: δ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2407. 
• MeSH delta+Opioid+Receptor