Delta Opioid receptor

The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as their endogenous ligands.cite journal | author = Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, Slate CA, Ehlert FJ, Roeske WR, Yamamura HI | title = The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy | journal = Pharmacol. Rev. | volume = 51 | issue = 3 | pages = 503–32 | year = 1999 | pmid = 10471416 | doi = | issn = | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/51/3/503 ]

Function

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,cite journal | author = Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC | title = 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 | journal = J. Med. Chem. | volume = 37 | issue = 14 | pages = 2125–8 | year = 1994 | pmid = 8035418 | doi = 10.1021/jm00040a002 | issn = ] the more potent (+)-BW373U86,cite journal | author = 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 | title = 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 | journal = J. Med. Chem. | volume = 40 | issue = 5 | pages = 695–704 | year = 1997 | pmid = 9057856 | doi = 10.1021/jm960319n | issn = ] a newer drug DPI-287 which does not produce the problems with convulsions seen with the earlier agents,cite journal | author = Jutkiewicz EM | title = The antidepressant -like effects of delta-opioid receptor agonists | journal = Mol. Interv. | volume = 6 | issue = 3 | pages = 162–9 | year = 2006 | pmid = 16809477 | doi = 10.1124/mi.6.3.7 | issn = ] and the mixed mu/delta agonist DPI-3290 which is a much more potent analgesic than the more highly selective delta agonists.cite journal | author = Ananthan S | title = Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics | journal = AAPS J | volume = 8 | issue = 1 | pages = E118–25 | year = 2006 | pmid = 16584118 | doi = 10.1208/aapsj080114 | issn = ] Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole.cite journal | author = Portoghese PS, Sultana M, Takemori AE | title = Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist | journal = Eur. J. Pharmacol. | volume = 146 | issue = 1 | pages = 185–6 | year = 1988 | pmid = 2832195 | doi = 10.1016/0014-2999(88)90502-X | issn = ]

Activation of delta receptors produces some analgesia, although less than that of mu-opioid agonists.cite journal | author = Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI | title = Agonist-specific regulation of the delta-opioid receptor | journal = Life Sci. | volume = 76 | issue = 6 | pages = 599–612 | year = 2004 | pmid = 15567186 | doi = 10.1016/j.lfs.2004.07.020 | issn = ] Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.cite journal | author = Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH | title = The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol | journal = J. Pharmacol. Exp. Ther. | volume = 317 | issue = 3 | pages = 1337–48 | year = 2006 | pmid = 16537798 | doi = 10.1124/jpet.105.095810 | issn = ]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep,cite journal | author = Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, Szeto HH | title = Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep | journal = Am. J. Obstet. Gynecol. | volume = 178 | issue = 2 | pages = 397–401 | year = 1998 | pmid = 9500506 | doi = | issn = | url = http://www.ajog.org/article/S0002-9378(98)80032-X/pdf ] 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.cite journal | author = Gallantine EL, Meert TF | title = A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80 | journal = Basic Clin. Pharmacol. Toxicol. | volume = 97 | issue = 1 | pages = 39–51 | year = 2005 | pmid = 15943758 | doi = 10.1111/j.1742-7843.2005.pto_07.x | issn = ] 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.cite journal | author = Su YF, McNutt RW, Chang KJ | title = Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception | journal = J. Pharmacol. Exp. Ther. | volume = 287 | issue = 3 | pages = 815–23 | year = 1998 | pmid = 9864259 | doi = | issn = | url = http://jpet.aspetjournals.org/cgi/content/abstract/287/3/815 ] 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 which may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs which might be much safer than the mu agonists currently used for pain relief.

Of most interest however is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effectscite journal | author = Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH | title = Behavioral effects of delta-opioid receptor agonists: potential antidepressants? | journal = Jpn. J. Pharmacol. | volume = 90 | issue = 1 | pages = 1–6 | year = 2002 | pmid = 12396021 | doi = 10.1254/jjp.90.1 | issn = ] and also upregulation of BDNF production in the brain in animal models of depression.cite journal | author = Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH | title = Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats | journal = Brain Res. | volume = 1069 | issue = 1 | pages = 172–81 | year = 2006 | pmid = 16364263 | doi = 10.1016/j.brainres.2005.11.005 | issn = ] These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors,cite journal | author = Zhang H, Torregrossa MM, Jutkiewicz EM, Shi YG, Rice KC, Woods JH, Watson SJ, Ko MC | title = Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects | journal = Eur. J. Neurosci. | volume = 23 | issue = 4 | pages = 984–94 | year = 2006 | pmid = 16519663 | doi = 10.1111/j.1460-9568.2006.04621.x | issn = ] and so can also be produced by enkephalinase inhibitors such as RB-101.cite journal | author = Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH | title = Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects | journal = Eur. J. Pharmacol. | volume = 531 | issue = 1-3 | pages = 151–9 | year = 2006 | pmid = 16442521 | doi = 10.1016/j.ejphar.2005.12.002 | issn = ]

Recent work indicates that exogenous ligands which activate the delta receptors mimic the phenomenon known as ischemic preconditioning.cite journal | author = Zhang J, Qian H, Zhao P, Hong SS, Xia Y | title = Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor | journal = Stroke | volume = 37 | issue = 4 | pages = 1094–9 | year = 2006 | pmid = 16514101 | doi = 10.1161/01.STR.0000206444.29930.18 | issn = ] 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.cite journal | author = Guo L, Zhang L, Zhang DC | title = [Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications] | language = Chinese | journal = Sheng li ke xue jin zhan [Progress in physiology] | volume = 36 | issue = 4 | pages = 333–6 | year = 2005 | pmid = 16408774 | doi = | issn = ]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Narita M, Funada M, Suzuki T |title=Regulations of opioid dependence by opioid receptor types. |journal=Pharmacol. Ther. |volume=89 |issue= 1 |pages= 1–15 |year= 2001 |pmid= 11316510 |doi=
*cite journal | author=Evans CJ, Keith DE, Morrison H, "et al." |title=Cloning of a delta opioid receptor by functional expression. |journal=Science |volume=258 |issue= 5090 |pages= 1952–5 |year= 1993 |pmid= 1335167 |doi=
*cite journal | author=Offermanns S, Schultz G, Rosenthal W |title=Evidence for opioid receptor-mediated activation of the G-proteins, Go and Gi2, in membranes of neuroblastoma x glioma (NG108-15) hybrid cells. |journal=J. Biol. Chem. |volume=266 |issue= 6 |pages= 3365–8 |year= 1991 |pmid= 1671672 |doi=
*cite journal | author=Simonin F, Befort K, Gavériaux-Ruff C, "et al." |title=The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain. |journal=Mol. Pharmacol. |volume=46 |issue= 6 |pages= 1015–21 |year= 1995 |pmid= 7808419 |doi=
*cite journal | author=Befort K, Mattéi MG, Roeckel N, Kieffer B |title=Chromosomal localization of the delta opioid receptor gene to human 1p34.3-p36.1 and mouse 4D bands by in situ hybridization. |journal=Genomics |volume=20 |issue= 1 |pages= 143–5 |year= 1994 |pmid= 8020949 |doi=
*cite journal | author=Knapp RJ, Malatynska E, Fang L, "et al." |title=Identification of a human delta opioid receptor: cloning and expression. |journal=Life Sci. |volume=54 |issue= 25 |pages= PL463–9 |year= 1994 |pmid= 8201839 |doi=
*cite journal | author=Georgoussi Z, Carr C, Milligan G |title=Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go. |journal=Mol. Pharmacol. |volume=44 |issue= 1 |pages= 62–9 |year= 1993 |pmid= 8393523 |doi=
*cite journal | author=Bzdega T, Chin H, Kim H, "et al." |title=Regional expression and chromosomal localization of the delta opiate receptor gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 20 |pages= 9305–9 |year= 1993 |pmid= 8415697 |doi=
*cite journal | author=Ho MK, Wong YH |title=Functional role of amino-terminal serine16 and serine27 of G alphaZ in receptor and effector coupling. |journal=J. Neurochem. |volume=68 |issue= 6 |pages= 2514–22 |year= 1997 |pmid= 9166747 |doi=
*cite journal | author=Hedin KE, Bell MP, Kalli KR, "et al." |title=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=J. Immunol. |volume=159 |issue= 11 |pages= 5431–40 |year= 1998 |pmid= 9548483 |doi=
*cite journal | author=Jordan BA, Devi LA |title=G-protein-coupled receptor heterodimerization modulates receptor function. |journal=Nature |volume=399 |issue= 6737 |pages= 697–700 |year= 1999 |pmid= 10385123 |doi= 10.1038/21441
*cite journal | author=Petaja-Repo UE, Hogue M, Laperriere A, "et al." |title=Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor. |journal=J. Biol. Chem. |volume=275 |issue= 18 |pages= 13727–36 |year= 2000 |pmid= 10788493 |doi=
*cite journal | author=Gelernter J, Kranzler HR |title=Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence. |journal=Hum. Genet. |volume=107 |issue= 1 |pages= 86–8 |year= 2000 |pmid= 10982041 |doi=
*cite journal | author=Guo J, Wu Y, Zhang W, "et al." |title=Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation. |journal=Mol. Pharmacol. |volume=58 |issue= 5 |pages= 1050–6 |year= 2000 |pmid= 11040053 |doi=
*cite journal | author=Gomes I, Jordan BA, Gupta A, "et al." |title=Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. |journal=J. Neurosci. |volume=20 |issue= 22 |pages= RC110 |year= 2001 |pmid= 11069979 |doi=
*cite journal | author=Xu W, Chen C, Huang P, "et al." |title=The conserved cysteine 7.38 residue is differentially accessible in the binding-site crevices of the mu, delta, and kappa opioid receptors. |journal=Biochemistry |volume=39 |issue= 45 |pages= 13904–15 |year= 2000 |pmid= 11076532 |doi=
*cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=
*cite journal | author=Saeed RW, Stefano GB, Murga JD, "et al." |title=Expression of functional delta opioid receptors in vascular smooth muscle. |journal=Int. J. Mol. Med. |volume=6 |issue= 6 |pages= 673–7 |year= 2001 |pmid= 11078827 |doi=
*cite journal | author=Xiang B, Yu GH, Guo J, "et al." |title=Heterologous activation of protein kinase C stimulates phosphorylation of delta-opioid receptor at serine 344, resulting in beta-arrestin- and clathrin-mediated receptor internalization. |journal=J. Biol. Chem. |volume=276 |issue= 7 |pages= 4709–16 |year= 2001 |pmid= 11085981 |doi= 10.1074/jbc.M006187200
*cite journal | author=Yeo A, Samways DS, Fowler CE, "et al." |title=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=J. Neurochem. |volume=76 |issue= 6 |pages= 1688–700 |year= 2001 |pmid= 11259487 |doi=

External links

* [http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2407 IUPHAR GPCR Database - δ opioid receptor]
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