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Gene Review

OPRD1  -  opioid receptor, delta 1

Homo sapiens

Synonyms: D-OR-1, DOR-1, Delta-type opioid receptor, OPRD
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Disease relevance of OPRD1

  • Using the polymerase chain reaction and primers based on the sequence of the cloned human delta-opioid receptor (hDOR) gene, we have obtained a full length cDNA encoding the hDOR from SH-SY5Y neuroblastoma cells [1].
  • Naltrindole, a selective DOR antagonist, abolished the increase in [Ca2+]i, and pretreatment with pertussis toxin was also effective [2].
  • Immunofluorescence detection of delta opioid receptors (DOR) on human peripheral blood CD4+ T cells and DOR-dependent suppression of HIV-1 expression [3].
  • We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K(+) homeostasis during anoxia or ischemia [4].
  • Using a burn wound model, significant wound healing delay (about 2 days) and severe epidermal hypertrophy were shown at the wound margin of DOR KO mice [5].

Psychiatry related information on OPRD1

  • Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN) [6].
  • The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence [7].
  • Therefore, these data do not support an association between the OPRD1 gene and heroin dependence in the Chinese population [8].

High impact information on OPRD1

  • Thus, the DOR expressed by a transfected Jurkat T-cell line is positively coupled to pathways leading to calcium mobilization and negatively coupled to adenylate cyclase [2].
  • The DOR agonists, deltorphin and [D-Ala2, D-Leu5]-enkephalin (DADLE), elevated [Ca2+]i, measured by flow cytofluorometry using the calcium-sensitive dye, Fluo-3 [2].
  • TNFalpha and IL-1beta both suppressed the expression of DOR and KOR mRNA in both OA and RA FLS [9].
  • The expression of KOR and DOR in OA and RA FLS was evaluated on the messenger RNA (mRNA) and protein levels with TaqMan real-time reverse transcriptase-polymerase chain reaction and immunofluorescence staining, respectively [9].
  • The presence of G-proteins increased the affinity of agonists to the hDOR, and caused faster binding kinetics and different ligand-induced conformational changes [10].

Chemical compound and disease context of OPRD1

  • Endogenous human delta-opioid receptors (hDOR) are differentially regulated in terms of desensitization by peptide ([d-Pen2,5]enkephalin (DPDPE) and Deltorphin I) and alkaloid (etorphine) agonists in the neuroblastoma cell line SK-N-BE (Allouche, S., Roussel, M., Marie, N., and Jauzac, P. (1999) Eur. J. Pharmacol. 371, 235-240) [11].
  • Forskolin-stimulated cAMP accumulation in the 293/DOR cells was dose-dependently suppressed by the delta-selective agonist [D-Pen2, D-Pen5]enkephalin, and such inhibition was abolished by pertussis toxin or the opiate antagonist naloxone [12].
  • To test this hypothesis, DOR-Ju.1 cells, derived from Jurkat cells stably transfected with a cDNA encoding the neuronal DOR, were stimulated with deltorphin or benzamide, 4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-methoxyphenyl)methyl]N- ,[2S[(S*),2alpha,5beta]]-(9Cl) (SNC-80) prior to the addition of HIV-1 [13].

Biological context of OPRD1

  • Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs [6].
  • Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence [7].
  • We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype [7].
  • Based on the genotype and allele frequencies of the genomic control loci, there was no evidence for stratification bias capable of masking an association of OPRD1 to heroin dependence in this large and homogenous Chinese sample [8].
  • Genotype and allele frequencies at OPRD1 921T > C were not significantly different, and the OPRD1 80G was absent from both Chinese opioid dependence patients and controls [8].

Anatomical context of OPRD1

  • We therefore created and studied a T cell line expressing the cloned delta-opioid receptor (DOR1) [14].
  • The delta agonists [D-Ala2, D-Leu5]enkephalin, cyclic [D-penicillamine2,D-penicillamine5]enkephalin, and BW373U86 efficiently decrease forskolin-induced cAMP levels in hDOR-expressing COS cells, indicating functional coupling of the receptor [1].
  • Using RT-PCR with primers to the cloned delta opioid receptor (DOR), a cDNA fragment identical to the known DOR sequence was obtained from the smooth muscle cell line, A-10 [15].
  • These data demonstrate the presence of a functional DOR in vascular smooth muscle and a direct impact of opioids on vascular contractile tone [15].
  • Recycling of the mu opioid receptor to the plasma membrane after endocytosis promotes rapid resensitization of signal transduction, whereas targeting of the delta opioid receptor (DOR) to lysosomes causes proteolytic down-regulation [16].

Associations of OPRD1 with chemical compounds

  • These data suggest that polymorphisms in both the serotonin 1D (HTR1D) and opioid delta 1 (OPRD1) receptor genes show a significant association with restricting AN (RAN) [17].
  • Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study [18].
  • Our result showed that removing the C terminus of delta opioid receptor (DOR) containing six Ser/Thr residues abolished both DPDPE- and phorbol 12-myristate 13-acetate (PMA)-induced DOR phosphorylation [19].
  • Activation of PKC by PMA, alpha(1A)-adrenergic receptor agonist, and ionomycin resulted in DOR internalization that required phosphorylation of Ser-344 [19].
  • The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis [20].

Physical interactions of OPRD1

  • Immunoprecipitation experiments demonstrated that beta-arrestin 1 physically interacts with delta opioid receptor (DOR) co-expressed in human embryonic kidney 293 cells in an agonist-enhanced manner and truncation of the carboxyl terminus of DOR partially impairs the interaction [21].

Regulatory relationships of OPRD1

  • Coexpression of GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions [22].
  • The current study investigated the role of receptor phosphorylation and the involvement of different beta-arrestin subtypes in agonist-induced delta-opioid receptor (DOR) internalization in HEK293 cells [23].

Other interactions of OPRD1

  • Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls [6].
  • We used mammalian cells transfected with each of the cDNA clones for the human receptors hMOR, hDOR, hKOR and showed that dynorphin A displaced [3H]-diprenorphine binding with Ki values in the nanomolar range at all three receptors [24].
  • Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus [22].
  • Surface plasmon resonance determination further revealed that binding of CT and I3L of DOR to beta-arrestin is additive, suggesting these two domains bind at distinctly different sites on beta-arrestin without considerable spatial hindrance [21].
  • The phosphorylation levels of DOR mutants T352A, T353A, and T358A/T361A/S363S were comparable to that of the wild-type DOR, whereas S344G substitution blocked PMA-induced receptor phosphorylation, indicating that PKC-mediated phosphorylation occurs at Ser-344 [19].

Analytical, diagnostic and therapeutic context of OPRD1

  • In this study, we first examined the distribution of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) in the amygdala via in situ hybridization and immunohistochemistry [25].
  • In this study, we report detection of MOR as well as DOR protein by immunohistochemical localization, and mRNA by fluorescent in situ hybridization (FISH) within Purkinje cells (PK) and the granular layer of neonatal (P6) and adult rat cerebellum [26].
  • Sustained activation by peptides for 30 min caused a marked decrease of both [3H]diprenorphine binding sites and hDOR immunoreactivity, observed in a Western blot, whereas a moderate reduction by 30% was observed after a 30- and 60-min etorphine exposure in binding experiments without opioid receptor degradation [11].
  • Quantitative assays using ELISA and flow cytometric techniques indicated that DOR344T receptors were endocytosed in HEK293 cells with similarly rapid kinetics as full-length DOR (t1/2 < 10 min), and both full-length DOR and DOR344T mutant receptors were endocytosed by a dynamin-dependent mechanism involving clathrin-coated pits [27].
  • This study determined the antinociceptive effects of DXM administered alone or in combination with morphine or the delta-opioid receptor (DOR) agonist SNC80 using a squirrel monkey titration procedure [28].


  1. The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain. Simonin, F., Befort, K., Gavériaux-Ruff, C., Matthes, H., Nappey, V., Lannes, B., Micheletti, G., Kieffer, B. Mol. Pharmacol. (1994) [Pubmed]
  2. Dual signal transduction through delta opioid receptors in a transfected human T-cell line. Sharp, B.M., Shahabi, N.A., Heagy, W., McAllen, K., Bell, M., Huntoon, C., McKean, D.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  3. Immunofluorescence detection of delta opioid receptors (DOR) on human peripheral blood CD4+ T cells and DOR-dependent suppression of HIV-1 expression. Sharp, B.M., McAllen, K., Gekker, G., Shahabi, N.A., Peterson, P.K. J. Immunol. (2001) [Pubmed]
  4. Cortical delta-opioid receptors potentiate K+ homeostasis during anoxia and oxygen-glucose deprivation. Chao, D., Donnelly, D.F., Feng, Y., Bazzy-Asaad, A., Xia, Y. J. Cereb. Blood Flow Metab. (2007) [Pubmed]
  5. Deletion of delta-opioid receptor in mice alters skin differentiation and delays wound healing. Bigliardi-Qi, M., Gaveriaux-Ruff, C., Zhou, H., Hell, C., Bady, P., Rufli, T., Kieffer, B., Bigliardi, P. Differentiation (2006) [Pubmed]
  6. Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. Bergen, A.W., van den Bree, M.B., Yeager, M., Welch, R., Ganjei, J.K., Haque, K., Bacanu, S., Berrettini, W.H., Grice, D.E., Goldman, D., Bulik, C.M., Klump, K., Fichter, M., Halmi, K., Kaplan, A., Strober, M., Treasure, J., Woodside, B., Kaye, W.H. Mol. Psychiatry (2003) [Pubmed]
  7. Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence. Gelernter, J., Kranzler, H.R. Hum. Genet. (2000) [Pubmed]
  8. Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Xu, K., Liu, X.H., Nagarajan, S., Gu, X.Y., Goldman, D. Am. J. Med. Genet. (2002) [Pubmed]
  9. Kappa and delta opioid receptors are expressed but down-regulated in fibroblast-like synoviocytes of patients with rheumatoid arthritis and osteoarthritis. Shen, H., Aeschlimann, A., Reisch, N., Gay, R.E., Simmen, B.R., Michel, B.A., Gay, S., Sprott, H. Arthritis Rheum. (2005) [Pubmed]
  10. Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. Alves, I.D., Ciano, K.A., Boguslavski, V., Varga, E., Salamon, Z., Yamamura, H.I., Hruby, V.J., Tollin, G. J. Biol. Chem. (2004) [Pubmed]
  11. Differential sorting of human delta-opioid receptors after internalization by peptide and alkaloid agonists. Marie, N., Lecoq, I., Jauzac, P., Allouche, S. J. Biol. Chem. (2003) [Pubmed]
  12. Inverse agonistic effect of ICI-174,864 on the cloned delta-opioid receptor: role of G protein and adenylyl cyclase activation. Chiu, T.T., Yung, L.Y., Wong, Y.H. Mol. Pharmacol. (1996) [Pubmed]
  13. Delta-opioid suppression of human immunodeficiency virus-1 expression in T cells (Jurkat). Sharp, B.M., Gekker, G., Li, M.D., Chao, C.C., Peterson, P.K. Biochem. Pharmacol. (1998) [Pubmed]
  14. 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. Hedin, K.E., Bell, M.P., Kalli, K.R., Huntoon, C.J., Sharp, B.M., McKean, D.J. J. Immunol. (1997) [Pubmed]
  15. Expression of functional delta opioid receptors in vascular smooth muscle. Saeed, R.W., Stefano, G.B., Murga, J.D., Short, T.W., Qi, F., Bilfinger, T.V., Magazine, H.I. Int. J. Mol. Med. (2000) [Pubmed]
  16. Modulation of postendocytic sorting of G protein-coupled receptors. Whistler, J.L., Enquist, J., Marley, A., Fong, J., Gladher, F., Tsuruda, P., Murray, S.R., Von Zastrow, M. Science (2002) [Pubmed]
  17. Further Evidence of Association of OPRD1 & HTR1D Polymorphisms with Susceptibility to Anorexia Nervosa. Brown, K.M., Bujac, S.R., Mann, E.T., Campbell, D.A., Stubbins, M.J., Blundell, J.E. Biol. Psychiatry (2007) [Pubmed]
  18. Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study. Gelernter, J., Gueorguieva, R., Kranzler, H.R., Zhang, H., Cramer, J., Rosenheck, R., Krystal, J.H. Alcohol. Clin. Exp. Res. (2007) [Pubmed]
  19. Heterologous activation of protein kinase C stimulates phosphorylation of delta-opioid receptor at serine 344, resulting in beta-arrestin- and clathrin-mediated receptor internalization. Xiang, B., Yu, G.H., Guo, J., Chen, L., Hu, W., Pei, G., Ma, L. J. Biol. Chem. (2001) [Pubmed]
  20. Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis. Kobayashi, H., Hata, H., Ujike, H., Harano, M., Inada, T., Komiyama, T., Yamada, M., Sekine, Y., Iwata, N., Iyo, M., Ozaki, N., Itokawa, M., Naka, M., Ide, S., Ikeda, K., Numachi, Y., Sora, I. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2006) [Pubmed]
  21. Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor. Cen, B., Yu, Q., Guo, J., Wu, Y., Ling, K., Cheng, Z., Ma, L., Pei, G. J. Neurochem. (2001) [Pubmed]
  22. Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation. Guo, J., Wu, Y., Zhang, W., Zhao, J., Devi, L.A., Pei, G., Ma, L. Mol. Pharmacol. (2000) [Pubmed]
  23. Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and -independent internalization of delta-opioid receptors. Zhang, X., Wang, F., Chen, X., Li, J., Xiang, B., Zhang, Y.Q., Li, B.M., Ma, L. J. Neurochem. (2005) [Pubmed]
  24. Dynorphin A as a potential endogenous ligand for four members of the opioid receptor gene family. Zhang, S., Tong, Y., Tian, M., Dehaven, R.N., Cortesburgos, L., Mansson, E., Simonin, F., Kieffer, B., Yu, L. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  25. Enkephalinergic afferents of the centromedial amygdala in the rat. Poulin, J.F., Chevalier, B., Laforest, S., Drolet, G. J. Comp. Neurol. (2006) [Pubmed]
  26. Abundant expression of mu and delta opioid receptor mRNA and protein in the cerebellum of the fetal, neonatal, and adult rat. Mrkusich, E.M., Kivell, B.M., Miller, J.H., Day, D.J. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  27. Phosphorylation is not required for dynamin-dependent endocytosis of a truncated mutant opioid receptor. Murray, S.R., Evans, C.J., von Zastrow, M. J. Biol. Chem. (1998) [Pubmed]
  28. Dextromethorphan potentiates the antinociceptive effects of morphine and the delta-opioid agonist SNC80 in squirrel monkeys. Allen, R.M., Granger, A.L., Dykstra, L.A. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
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