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Gene Review

Oprd1  -  opioid receptor, delta 1

Mus musculus

Synonyms: D-OR-1, DOR, DOR-1, Delta-type opioid receptor, K56, ...
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Disease relevance of Oprd1

  • However, the development of mechanical and thermal allodynia, and thermal hyperalgesia was significantly enhanced in DOR knockout mice [1].
  • By exchanging the carboxyl tail domains of MOR and DOR and expressing the receptor chimeras in mouse neuroblastoma Neuro2A cells, it could be demonstrated that the carboxyl tail domain is not the sole determinant in directing the intracellular trafficking in these Neuro2A cells [2].
  • In the present study, we analyzed a 1.3-kb DNA fragment immediately upstream of the translation start site (-1300 to +1 bp, with the translation start site designated as +1) of the mouse DOR gene in EL-4 cells, a mouse lymphoma T cell line that exhibits enhanced expression of DOR transcripts when activated by phytohemagglutinin [3].
  • More importantly, the C352L mutant of Galpha(i2) remained associated with DOR after long-term agonist and pertussis toxin treatment whereas the wild-type Galpha(i2) did not [4].
  • Using mouse delta opioid receptor (DOR) cDNA sequence to probe genomic libraries in bacteriophage lambda and P1 vectors, clones traversing the entire DOR coding sequence and 5' and 3' flanking regions were isolate [5].

Psychiatry related information on Oprd1

  • We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders [6].

High impact information on Oprd1

  • Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance [7].
  • Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown [7].
  • The mu-, delta- and kappa- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids [6].
  • Here we describe a novel mechanism for plasma membrane insertion of the delta opioid receptor (DOR) [8].
  • Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide delta agonist BW373U69 exhibits enhanced activity in DOR-1 mutant mice [9].

Chemical compound and disease context of Oprd1


Biological context of Oprd1

  • The observation of opposing phenotypes of MOR- and DOR-deficient mice in several behaviors highlights unexpected roles for DOR to be further explored genetically and using more specific delta compounds [11].
  • Here we show that the mouse delta-opioid receptor (mDOR) gene is regulated by promoter region CpG methylation [12].
  • In vitro protein-DNA binding assays and in vivo transient transfection assays indicated that members of both the upstream stimulatory factor and Sp families of transcription factors bound to and trans-activated the DOR promoter via the E box and GC box, respectively [13].
  • In addition, in vitro methylation of the luciferase reporter gene driven by the mDOR promoter resulted in an inhibition of transcription in NS20Y cells [12].
  • In DOR-1 mutant mice, improgan was equally effective in all three genotypes, despite the reduction (+/-) or complete loss (-/-) of delta opioid receptor (3H-[D-Pen(2), D-Pen(5)]enkephalin, DPDPE) binding [14].

Anatomical context of Oprd1

  • Considerable evidence indicates that transcription of the delta-opioid receptor (dor) gene is correlated with both the expression of DOR on T cells and the capacity of DOR agonists to modulate the immunological functions of the T cell [15].
  • Here, we report the identification of a minimum core promoter, in the 5'-flanking region of the mouse DOR gene, containing an E box and a GC box that are crucial for DOR promoter activity in NS20Y cells, a DOR-expressing mouse neuronal cell line [13].
  • DOR activity first appeared at e17.5 in the hypothalamus, pons, medial habenula, and medulla and at p1 in the CPU at levels noticeably less than those of the MOR [16].
  • In wild-type and DOR knockout mice, sciatic nerve injury led to a neuropathic pain syndrome revealed in these nociceptive behavioural tests [1].
  • The antiexudative effects of KOR and DOR agonists in animals treated with nitric oxide synthase (NOS) inhibitors and their protein levels in the gut (whole jejunum and mucosa) and spinal cord of mice with chronic intestinal inflammation were also measured [17].

Associations of Oprd1 with chemical compounds

  • Repression of mDOR transcription in Neuro2A cells could be partially relieved by chemically induced demethylation with 5-aza-2'-deoxycytidine [12].
  • This interaction is mediated by the substance P domain of protachykinin and the third luminal domain of DOR [7].
  • In current studies, the nature of the heterodimers was investigated by producing the phenotypes of the 1:1 heterodimers formed between the constitutively expressed mu-opioid receptor (MOR) and the ponasterone A-induced expression of delta-opioid receptor (DOR) in EcR293 cells [18].
  • On the other hand, although the equivalent mutation of Asp95 to alanine in DOR likewise resulted in the inability of DPDPE to inhibit [3H]cAMP production, the ability of DPDPE to down-regulate this mutant receptor after 24-hr treatment was unaffected [19].
  • In addition, trichostatin A treatment increased both methylated mDOR promoter activity in a transient transfection assay and endogenous mDOR mRNA level in Neuro2A cells [20].

Regulatory relationships of Oprd1

  • In addition, the Ets-1 DNA-binding domain is sufficient to play the functional role of Ets-1 in trans-activating the DOR promoter [21].
  • The locomotor activating effects of a low dose (10 mg/kg) of cocaine were enhanced in DOR KO mice whereas the locomotor activating effects of both a low and higher (20 mg/kg) dose of cocaine were reduced in MOR KO animals [22].

Other interactions of Oprd1

  • Furthermore, the expression level of Sp3 was decreased when Neuro2A cells were demethylated with 5-aza-2'-deoxycytidine, and increasing Sp3 levels in Schneider's Drosophila line 2 cells led to the repression of mDOR promoter activity when the promoter was methylated [12].
  • These data demonstrate that although signaling pathways involving ppENK, DOR, and NMDA receptor are necessary for the expression of morphine tolerance, other pathways independent of these factors can mediate physical dependence [23].
  • Collectively, our data suggest that Ets-1 functions as a trans-activator of the DOR promoter in the neonatal mouse brain and thus may contribute to the development of the mouse brain DOR system [21].
  • The mDOR promoter containing a putative CpG island is highly methylated in Neuro2A cells, correlating with the repression of this gene in these cells [12].
  • Chromatin immunoprecipitation analysis showed the association of a methyl-CpG-binding domain protein 2 (MBD2) with methylated mDOR promoter [20].

Analytical, diagnostic and therapeutic context of Oprd1


  1. Neuropathic pain is enhanced in delta-opioid receptor knockout mice. Nadal, X., Baños, J.E., Kieffer, B.L., Maldonado, R. Eur. J. Neurosci. (2006) [Pubmed]
  2. The intracellular trafficking of opioid receptors directed by carboxyl tail and a di-leucine motif in Neuro2A cells. Wang, W., Loh, H.H., Law, P.Y. J. Biol. Chem. (2003) [Pubmed]
  3. Transcriptional regulation of mouse delta-opioid receptor gene. Role of Ikaros in the stimulated transcription of mouse delta-opioid receptor gene in activated T cells. Sun, P., Loh, H.H. J. Biol. Chem. (2002) [Pubmed]
  4. Short- and long-term regulation of adenylyl cyclase activity by delta-opioid receptor are mediated by Galphai2 in neuroblastoma N2A cells. Zhang, L., Tetrault, J., Wang, W., Loh, H.H., Law, P.Y. Mol. Pharmacol. (2006) [Pubmed]
  5. Genomic structure of the mouse delta opioid receptor gene. Augustin, L.B., Felsheim, R.F., Min, B.H., Fuchs, S.M., Fuchs, J.A., Loh, H.H. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  6. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Filliol, D., Ghozland, S., Chluba, J., Martin, M., Matthes, H.W., Simonin, F., Befort, K., Gavériaux-Ruff, C., Dierich, A., LeMeur, M., Valverde, O., Maldonado, R., Kieffer, B.L. Nat. Genet. (2000) [Pubmed]
  7. Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Guan, J.S., Xu, Z.Z., Gao, H., He, S.Q., Ma, G.Q., Sun, T., Wang, L.H., Zhang, Z.N., Lena, I., Kitchen, I., Elde, R., Zimmer, A., He, C., Pei, G., Bao, L., Zhang, X. Cell (2005) [Pubmed]
  8. Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Bao, L., Jin, S.X., Zhang, C., Wang, L.H., Xu, Z.Z., Zhang, F.X., Wang, L.C., Ning, F.S., Cai, H.J., Guan, J.S., Xiao, H.S., Xu, Z.Q., He, C., Hökfelt, T., Zhou, Z., Zhang, X. Neuron (2003) [Pubmed]
  9. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Zhu, Y., King, M.A., Schuller, A.G., Nitsche, J.F., Reidl, M., Elde, R.P., Unterwald, E., Pasternak, G.W., Pintar, J.E. Neuron (1999) [Pubmed]
  10. Activation of N-methyl-D-aspartate receptor attenuates acute responsiveness of delta-opioid receptors. Cai, Y.C., Ma, L., Fan, G.H., Zhao, J., Jiang, L.Z., Pei, G. Mol. Pharmacol. (1997) [Pubmed]
  11. Exploring the opioid system by gene knockout. Kieffer, B.L., Gavériaux-Ruff, C. Prog. Neurobiol. (2002) [Pubmed]
  12. Transcriptional regulation of mouse delta-opioid receptor gene by CpG methylation: involvement of Sp3 and a methyl-CpG-binding protein, MBD2, in transcriptional repression of mouse delta-opioid receptor gene in Neuro2A cells. Wang, G., Wei, L.N., Loh, H.H. J. Biol. Chem. (2003) [Pubmed]
  13. Transcriptional regulation of mouse delta-opioid receptor gene. Liu, H.C., Shen, J.T., Augustin, L.B., Ko, J.L., Loh, H.H. J. Biol. Chem. (1999) [Pubmed]
  14. Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice. Hough, L.B., Nalwalk, J.W., Chen, Y., Schuller, A., Zhu, Y., Zhang, J., Menge, W.M., Leurs, R., Timmerman, H., Pintar, J.E. Brain Res. (2000) [Pubmed]
  15. Transcriptional regulation of mouse delta-opioid receptor gene. Ikaros-2 and upstream stimulatory factor synergize in trans-activating mouse delta-opioid receptor gene in T cells. Sun, P., Loh, H.H. J. Biol. Chem. (2003) [Pubmed]
  16. Opioid receptor-induced GTPgamma35S binding during mouse development. Nitsche, J.F., Pintar, J.E. Dev. Biol. (2003) [Pubmed]
  17. Antiexudative effects of opioids and expression of kappa- and delta-opioid receptors during intestinal inflammation in mice: involvement of nitric oxide. Jiménez, N., Puig, M.M., Pol, O. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  18. Heterodimerization of mu- and delta-opioid receptors occurs at the cell surface only and requires receptor-G protein interactions. Law, P.Y., Erickson-Herbrandson, L.J., Zha, Q.Q., Solberg, J., Chu, J., Sarre, A., Loh, H.H. J. Biol. Chem. (2005) [Pubmed]
  19. The mu-opioid receptor down-regulates differently from the delta-opioid receptor: requirement of a high affinity receptor/G protein complex formation. Chakrabarti, S., Yang, W., Law, P.Y., Loh, H.H. Mol. Pharmacol. (1997) [Pubmed]
  20. DNA methylation-related chromatin modification in the regulation of mouse delta-opioid receptor gene. Wang, G., Liu, T., Wei, L.N., Law, P.Y., Loh, H.H. Mol. Pharmacol. (2005) [Pubmed]
  21. Transcriptional regulation of mouse delta-opioid receptor gene: role of Ets-1 in the transcriptional activation of mouse delta-opioid receptor gene. Sun, P., Loh, H.H. J. Biol. Chem. (2001) [Pubmed]
  22. Contrasting effects of mu opioid receptor and delta opioid receptor deletion upon the behavioral and neurochemical effects of cocaine. Chefer, V.I., Kieffer, B.L., Shippenberg, T.S. Neuroscience (2004) [Pubmed]
  23. Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. Nitsche, J.F., Schuller, A.G., King, M.A., Zengh, M., Pasternak, G.W., Pintar, J.E. J. Neurosci. (2002) [Pubmed]
  24. Quantitative autoradiographic mapping of opioid receptors in the brain of delta-opioid receptor gene knockout mice. Goody, R.J., Oakley, S.M., Filliol, D., Kieffer, B.L., Kitchen, I. Brain Res. (2002) [Pubmed]
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