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Gene Review

Oprm1  -  opioid receptor, mu 1

Mus musculus

Synonyms: M-OR-1, MOP receptor, MOP-R, MOR-1, MOR-1O, ...
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Disease relevance of Oprm1

  • The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD) [1].
  • This increase is probably mediated through modification of the chromatin structure, as suggested by the reversal of the PU.1-mediated repression of MOR promoter activity after trichostatin A treatment in neuroblastoma NMB cells [2].
  • This poly (A) is much less effective for a heterologous promoter, such as simian virus 40, indicating a functional coupling of MOR promoter and its own poly (A) [3].
  • BACKGROUND: The involvement of the mu-opioid receptor (muOR) system in the control of breathing, anesthetic potency, and morphine- and anesthesia-induced respiratory depression was investigated in mice lacking the muOR [4].
  • Blockade of delta-opioid receptors with naltrindole affected neither the ventilatory patterns nor the ventilatory responses to hypoxia in MOR-/- and wild-type mice [5].

Psychiatry related information on Oprm1

  • Increasing evidence suggests that differences in Oprm1 gene sequences affect the amount of Oprm1 mRNA and sensitivity to opiates, and >100 polymorphisms have been identified in the human OPRM1 gene, some of which are related to vulnerability to drug dependence in some populations [6].
  • Because our previous studies of MOR-deficient mice have shown that this receptor protein is also responsible for morphine analgesia, reward, and physical dependence, the present results imply that MOR-targeted therapeutic drugs that are developed for the treatment of pain or opiate addiction may concomitantly influence immune responses [7].
  • Assessments of individual differences in human muOR expression add further support [8].
  • This supports the hypothesis that naloxone-induced withdrawal symptoms result at least in part from suppression of basal signaling activity of MOR in morphine-dependent animals [9].

High impact information on Oprm1

  • Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired [10].
  • The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR) [10].
  • Exposure to an environment previously associated with rewarding properties of nicotine results in an increase of CREB phosphorylation similar to that seen following nicotine administration, and this response is absent in MOR(-/-) mice [11].
  • Morphine analgesic properties and side effects such as tolerance are mediated by the mu opioid receptor (MOR) whose endocytosis is considered of primary importance for opioid pharmacological effects [12].
  • Using 5' RACE, we have isolated four additional exons of the mu opioid receptor gene (Oprm), resulting in a gene spanning over 250 kb [13].

Chemical compound and disease context of Oprm1

  • Unrestrained MOR-/- and wild-type mice showed similar ventilatory patterns at rest and similar chemosensory responses to hyperoxia (100% O2), hypoxia (10% O2) or hypercapnia (5%CO2-95%O2) [5].
  • When fed a high-fat diet, MOR(-/-) mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice [14].
  • We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT) [15].

Biological context of Oprm1

  • Improgan (30 microg, icv) induced reversible, maximal analgesia in both sexes of all three genotypes (+/+, +/- and -/-) of MOR-1 mutant mice 10 and 20 min after administration, whereas morphine analgesia was reduced (+/-) or abolished (-/-) in these subjects [16].
  • In mouse Oprm1, exon 18 is located between the described exons 10 and 6 [17].
  • The mouse MOR gene is > 53 kb long, and the coding sequence is divided by three introns, with exon junctions in codons 95 and 213 and between codons 386 and 387 [18].
  • Studies with mice, including knockout-transgenic, quantitative trait locus, and strain-comparison studies, also strongly support the possibility that muOR gene alleles would be strong candidates for contributing to individual differences in human nociception and opiate drug responses [8].
  • We have isolated mouse mu opioid receptor genomic clones (termed MOR) containing the entire amino acid coding sequence corresponding to rat MOR-1 cDNA, including additional 5' flanking sequence [18].

Anatomical context of Oprm1

  • MOR activation was first detected in the caudate-putamen (CPU) at e12.5, and by e15.5, activity had not only increased in this region but also expanded to include the midbrain, medial habenula, hypothalamus, pons, and medulla [19].
  • 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 [19].
  • Together with the increased exploratory activity we established in homozygous mice significantly increased expression of the Oprm1 gene in the frontal cortex and mesencephalon [20].
  • This demonstrates that the MOR gene product represents a major molecular target for morphine action on the immune system [7].
  • In mouse periaqueductal gray matter (PAG) membranes, the mu-opioid receptor (MOR) coprecipitated the alpha-subunits of the Gi/o/z/q/11 proteins, the Gbeta1/2 subunits, and the regulator of G-protein signaling RGS9-2 and its partner protein Gbeta5 [21].

Associations of Oprm1 with chemical compounds

  • Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock-out (-/-) mice [22].
  • 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 [23].
  • For example, morphine binding produces a muOR with low affinity for beta-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors [24].
  • When Asp114 in transmembrane 2 of MOR was converted to alanine, the ability was abolished of DAMGO or morphine to inhibit forskolin-stimulated [3H]cAMP production in Neuro2A cells stably expressing this mutant receptor [25].
  • Wild-type and mu-opioid receptor knockout (MORKO) mice were used to investigate the role of corticosterone (CORT) and the mu-opioid receptor (MOR) in chronic morphine-mediated immunosuppression [26].

Physical interactions of Oprm1


Regulatory relationships of Oprm1

  • These results suggest that Sox18 directly and specifically stimulates mor gene expression, by trans-activating the mor DP enhancer [27].
  • In co-transfection studies PU.1 represses MOR promoter reporter constructs through its PU.1 binding site [2].
  • 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 [28].

Other interactions of Oprm1

  • MOR mRNA was increased 24h after injection in Z and ZM groups, while KOR mRNA was similar in all groups except of decrease in Z at 24h [29].
  • In contrast, overexpression of another Sox member, Sox5, triggered no such trans-activation of mor DP-driven luciferase activity or DNA-protein binding activity [27].
  • Here we have identified a positive regulatory element influencing mor DP transcription, which contains multiple consensus binding motifs for Sox factors (sex-determining Sry-like high mobility group box-containing genes) [27].
  • The results clearly show that morphine-induced immunosuppression is mediated by the MOR and that although some functions are amplified in the presence of CORT or sympathetic activation, the inhibition of IFN-gamma synthesis and activation of macrophage-cytokine synthesis is CORT-independent and only partially dependent on sympathetic activation [26].
  • Nerve injury significantly reduced the expression of MOR in the DRG and the lumbar section of the spinal cord from CB1 cannabinoid knockout (KO) mice and wild-type littermates (WT) [30].

Analytical, diagnostic and therapeutic context of Oprm1

  • To investigate whether the mu-opioid receptor is functionally implicated in morphine immunosuppression in vivo, we have examined immune responses of mice with a genetic disruption of the MOR gene [7].
  • We have also determined endogenous PU.1 interactions with the 34-bp element of MOR promoter by chromatin immunoprecipitation assays [2].
  • In this study, we found that probes of regions essential for the production of functional MOR, as well as that of the 3'-downstream region of the MOR gene coding region, detected by Northern blot analyses, a major species of mature transcript MOR1 from mouse brain of approximately 11.5 kilobases (kb) [3].
  • The requirement of functional MOR but not DOR in agonist-induced receptor down-regulation was further demonstrated by site-directed mutagenesis of the receptors [25].
  • Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors [31].


  1. Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation. Philippe, D., Dubuquoy, L., Groux, H., Brun, V., Chuoï-Mariot, M.T., Gaveriaux-Ruff, C., Colombel, J.F., Kieffer, B.L., Desreumaux, P. J. Clin. Invest. (2003) [Pubmed]
  2. Transcriptional regulation of mouse mu opioid receptor gene by PU.1. Hwang, C.K., Kim, C.S., Choi, H.S., McKercher, S.R., Loh, H.H. J. Biol. Chem. (2004) [Pubmed]
  3. A major species of mouse mu-opioid receptor mRNA and its promoter-dependent functional polyadenylation signal. Wu, Q., Hwang, C.K., Yao, S., Law, P.Y., Loh, H.H., Wei, L.N. Mol. Pharmacol. (2005) [Pubmed]
  4. Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice. Dahan, A., Sarton, E., Teppema, L., Olievier, C., Nieuwenhuijs, D., Matthes, H.W., Kieffer, B.L. Anesthesiology (2001) [Pubmed]
  5. Respiratory function in adult mice lacking the mu-opioid receptor: role of delta-receptors. Morin-Surun, M.P., Boudinot, E., Dubois, C., Matthes, H.W., Kieffer, B.L., Denavit-Saubié, M., Champagnat, J., Foutz, A.S. Eur. J. Neurosci. (2001) [Pubmed]
  6. How individual sensitivity to opiates can be predicted by gene analyses. Ikeda, K., Ide, S., Han, W., Hayashida, M., Uhl, G.R., Sora, I. Trends Pharmacol. Sci. (2005) [Pubmed]
  7. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Gavériaux-Ruff, C., Matthes, H.W., Peluso, J., Kieffer, B.L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Uhl, G.R., Sora, I., Wang, Z. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  9. Inverse agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence. Wang, D., Raehal, K.M., Bilsky, E.J., Sadée, W. J. Neurochem. (2001) [Pubmed]
  10. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Bohn, L.M., Lefkowitz, R.J., Gainetdinov, R.R., Peppel, K., Caron, M.G., Lin, F.T. Science (1999) [Pubmed]
  11. Mu-opioid receptor and CREB activation are required for nicotine reward. Walters, C.L., Cleck, J.N., Kuo, Y.C., Blendy, J.A. Neuron (2005) [Pubmed]
  12. Phosphorylation of EEA1 by p38 MAP kinase regulates mu opioid receptor endocytosis. Macé, G., Miaczynska, M., Zerial, M., Nebreda, A.R. EMBO J. (2005) [Pubmed]
  13. Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene. Pan, Y.X., Xu, J., Mahurter, L., Bolan, E., Xu, M., Pasternak, G.W. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  14. Resistance to Diet-Induced Obesity in {micro}-Opioid Receptor-Deficient Mice: Evidence for a "Thrifty Gene". Tabarin, A., Chaves, Y.D., Carmona, M.d.e.l. .C., Catargi, B., Zorrilla, E.P., Roberts, A.J., Coscina, D.V., Rousset, S., Redonnet, A., Parker, G.C., Inoue, K., Ricquier, D., Pénicaud, L., Kieffer, B.L., Koob, G.F. Diabetes (2005) [Pubmed]
  15. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Sarton, E., Teppema, L.J., Olievier, C., Nieuwenhuijs, D., Matthes, H.W., Kieffer, B.L., Dahan, A. Anesth. Analg. (2001) [Pubmed]
  16. 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]
  17. Identification of three mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Doyle, G.A., Rebecca Sheng, X., Lin, S.S., Press, D.M., Grice, D.E., Buono, R.J., Ferraro, T.N., Berrettini, W.H. Gene (2007) [Pubmed]
  18. Genomic structure analysis of promoter sequence of a mouse mu opioid receptor gene. Min, B.H., Augustin, L.B., Felsheim, R.F., Fuchs, J.A., Loh, H.H. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  19. Opioid receptor-induced GTPgamma35S binding during mouse development. Nitsche, J.F., Pintar, J.E. Dev. Biol. (2003) [Pubmed]
  20. Cat odour exposure decreases exploratory activity and alters neuropeptide gene expression in CCK(2) receptor deficient mice, but not in their wild-type littermates. Areda, T., Raud, S., Philips, M.A., Innos, J., Matsui, T., Kõks, S., Vasar, E., Karis, A., Asser, T. Behav. Brain Res. (2006) [Pubmed]
  21. Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization. Garzón, J., Rodríguez-Muñoz, M., López-Fando, A., Sánchez-Blázquez, P. J. Biol. Chem. (2005) [Pubmed]
  22. Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons. Macey, T.A., Lowe, J.D., Chavkin, C. J. Biol. Chem. (2006) [Pubmed]
  23. 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]
  24. An opioid agonist that does not induce micro-opioid receptor--arrestin interactions or receptor internalization. Groer, C.E., Tidgewell, K., Moyer, R.A., Harding, W.W., Rothman, R.B., Prisinzano, T.E., Bohn, L.M. Mol. Pharmacol. (2007) [Pubmed]
  25. 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]
  26. The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor. Wang, J., Charboneau, R., Balasubramanian, S., Barke, R.A., Loh, H.H., Roy, S. J. Leukoc. Biol. (2002) [Pubmed]
  27. Transcriptional modulation of mouse mu-opioid receptor distal promoter activity by Sox18. Im, H.J., Smirnov, D., Yuhi, T., Raghavan, S., Olsson, J.E., Muscat, G.E., Koopman, P., Loh, H.H. Mol. Pharmacol. (2001) [Pubmed]
  28. 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]
  29. Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice. Chadzinska, M., Starowicz, K., Scislowska-Czarnecka, A., Bilecki, W., Pierzchala-Koziec, K., Przewlocki, R., Przewlocka, B., Plytycz, B. Immunol. Lett. (2005) [Pubmed]
  30. Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain. Pol, O., Murtra, P., Caracuel, L., Valverde, O., Puig, M.M., Maldonado, R. Neuropharmacology (2006) [Pubmed]
  31. Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice. Chefer, V.I., Kieffer, B.L., Shippenberg, T.S. Eur. J. Neurosci. (2003) [Pubmed]
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