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OPRM1  -  opioid receptor, mu 1

Homo sapiens

Synonyms: LMOR, M-OR-1, MOP, MOR, MOR-1, ...
 
 
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Disease relevance of OPRM1

  • OBJECTIVE: To replicate and extend the previously reported association between the opioid receptor mu subunit gene (OPRM1) and idiopathic absence epilepsy (IAE), using a sample of 230 probands with idiopathic generalized epilepsy (IGE) [1].
  • Pharmacological and autoradiological studies suggest that mu-opioid receptor (OPRM) mediated neurotransmission is involved in the generation of absence seizures [2].
  • Functional communication between these receptors is revealed by alpha(2A)-AR activation of a pertussis toxin-insensitive G(i)alpha subunit (termed as G(i)1) when fused with the MOR and evaluated in membranes from pertussis toxin-treated cells [3].
  • Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain [4].
  • This mechanism-based finding provides functional evidence in support of the clinical potential of KOR agonists as antipruritics in the presence of MOR agonist-induced pruritus [5].
 

Psychiatry related information on OPRM1

  • Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions [6].
  • Since 3'UTRs affect gene expression, the present characterization of the 3' noncoding region in the human OPRM1 gene should lead to a better understanding of the mechanisms underlying OPRM1 gene regulation and individual differences in sensitivity to opioids [7].
  • Mu opioid receptors are critical for heroin dependence, and A118G SNP of the mu opioid receptor gene (OPRM1) has been linked with heroin abuse [8].
  • Phenotypes other than a broad diagnostic categorization, such as opioid antagonist effects on drinking behavior in alcoholics, may provide more consistent evidence of a role for OPRM1 in behavioral variability [9].
  • BACKGROUND: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu (OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence [10].
 

High impact information on OPRM1

  • We report here that MOR mutations that facilitate endocytosis reduce the development of cellular tolerance and cAMP superactivation, a cellular hallmark of withdrawal [11].
  • Ser(375) phosphorylation was sufficient and required for morphine-induced desensitization of MOR [12].
  • Postmortem brain analyses showed the OPRM1 genotype associated with transcription, translation, and processing of the human striatal opioid neuropeptide system [8].
  • We examined 13 single nucleotide polymorphisms (SNPs) spanning the coding region of the micro-opioid receptor gene (OPRM1), among 382 European Americans (EAs) affected with substance dependence [alcohol dependence (AD) and/or drug dependence (DD)] and 338 EA healthy controls [13].
  • Association between two {micro}-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence [13].
 

Chemical compound and disease context of OPRM1

 

Biological context of OPRM1

  • Moreover, IL1R2 (P=0.002 in Blacks), NOS2A (P<0.001 in Whites) and OPRM1 (P=0.004 in Hispanics) gene haplotypes were associated with PTD in specific ethnic groups but not at global significance level [16].
  • Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay [6].
  • OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (US Caucasian [USC, n=100], Finnish Caucasian [FC, n=324] and Southwestern American Indian [SAI, n=367]), were used to perform association and sib-pair linkage analyses with alcohol and drug dependence diagnoses [17].
  • We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect function and/or be associated with psychiatric phenotypes related to opioid function [17].
  • While these data do not support a role of the mu opioid receptor in susceptibility to alcohol dependence, the potential relationship between OPRM1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated [17].
 

Anatomical context of OPRM1

  • Using a yeast two-hybrid screen, the rat mu-opioid receptor (MOR1, also termed MOP) was found to be associated with phospholipase D2 (PLD2), a phospholipid-specific phosphodiesterase located in the plasma membrane, which has been implicated in the formation of endocytotic vesicles [18].
  • To determine the sites in the mu-opioid receptor (MOR) critical for agonist-dependent desensitization, we constructed and coexpressed MORs lacking potential phosphorylation sites along with G-protein activated inwardly rectifying potassium channels composed of K(ir)3.1 and K(ir)3.4 subunits in Xenopus oocytes [19].
  • Furthermore, total-MOR immunoreactivity was not changed in the spinal cord of ethanol-fed rats [20].
  • Co-localization of GABA and MOR receptors was observed in neurons and nerve terminals in the central nucleus, dorsal cortex and external cortex of the inferior colliculus [21].
  • Our results indicate that the centromedial amygdala receives ENK afferents, as indicated by the presence of MOR, DOR, and ENK fibers in the CEA and MEA, originating primarily from the bed nucleus of the stria terminalis (BST) and from other amygdaloid nuclei [22].
 

Associations of OPRM1 with chemical compounds

  • Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study [23].
  • Human mu-opioid receptor (OPRM1) is the major site for the analgesic action of most opioid drugs such as morphine, methadone and heroin [24].
  • Other examples of the successful application of AEI analysis for studying functional polymorphism include 5-HTT (serotonin transporter, SLC6A4) and OPRM1 (mu opioid receptor) [25].
  • Treatment with the mu receptor agonist DAMGO ([d-Ala(2), Me Phe(4), Glyol(5)]enkephalin) led to an increase in PLD2 activity, whereas morphine, which does not induce MOR1 receptor internalization, failed to induce PLD2 activation [18].
  • Conversely the inhibition of PLD2-mediated phosphatidic acid formation by 1-butanol or overexpression of a negative mutant of PLD2 prevented agonist-mediated endocytosis of MOR1 [18].
 

Regulatory relationships of OPRM1

  • Furthermore, we performed refined mapping to elucidate the core region (-317/-304) involved in mediating the PCBP-induced MOR promoter activity [26].
  • Coexpression with either GRK3 or arr3 individually did not significantly enhance desensitization of responses evoked by wild type MOR activation [19].
  • Interestingly, the modified MOR is expressed at six times higher levels than wild-type MOR and is similarly stable as wild-type KOR after immobilization [27].
 

Other interactions of OPRM1

  • 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 [28].
  • 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 [29].
  • All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A [30].
  • These results suggest that OPRM1 118G in addition to ALDH2 1510G might be one of the risk factors for alcohol dependence in Japanese people [31].
  • However, the authors found no evidence for a specific association between OPRM1 and idiopathic absence epilepsy [1].
 

Analytical, diagnostic and therapeutic context of OPRM1

  • Using denaturing high performance liquid chromatography (DHPLC) the complete coding region of the OPRM1 gene was screened for SNPs in Han-Chinese heroin addicts and normal control [24].
  • The nuclear run-off assay and semiquantitative RT-PCR shows that PCBPs enhance the transcription rate of MOR gene [26].
  • Chromatin immunoprecipitation assay confirmed the interaction of PCBPs with MOR promoter in vivo [26].
  • In Northern blotting with mouse brain mRNAs, a same-size band was detected by a probe for the MOR-1 coding region and by a probe for a mouse genome region corresponding to the human MOR-1 3'UTR [7].
  • Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994) [32].

References

  1. Association of mu-opioid receptor subunit gene and idiopathic generalized epilepsy. Wilkie, H., Osei-Lah, A., Chioza, B., Nashef, L., McCormick, D., Asherson, P., Makoff, A.J. Neurology (2002) [Pubmed]
  2. Genetic variation of the human mu-opioid receptor and susceptibility to idiopathic absence epilepsy. Sander, T., Berlin, W., Gscheidel, N., Wendel, B., Janz, D., Hoehe, M.R. Epilepsy Res. (2000) [Pubmed]
  3. Hetero-oligomers of alpha2A-adrenergic and mu-opioid receptors do not lead to transactivation of G-proteins or altered endocytosis profiles. Zhang, Y.Q., Limbird, L.E. Biochem. Soc. Trans. (2004) [Pubmed]
  4. The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Lerman, C., Wileyto, E.P., Patterson, F., Rukstalis, M., Audrain-McGovern, J., Restine, S., Shields, P.G., Kaufmann, V., Redden, D., Benowitz, N., Berrettini, W.H. Pharmacogenomics J. (2004) [Pubmed]
  5. Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys. Ko, M.C., Lee, H., Song, M.S., Sobczyk-Kojiro, K., Mosberg, H.I., Kishioka, S., Woods, J.H., Naughton, N.N. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  6. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. Zhang, Y., Wang, D., Johnson, A.D., Papp, A.C., Sadée, W. J. Biol. Chem. (2005) [Pubmed]
  7. Characterization of the 3' untranslated region of the human mu-opioid receptor (MOR-1) mRNA. Ide, S., Han, W., Kasai, S., Hata, H., Sora, I., Ikeda, K. Gene (2005) [Pubmed]
  8. Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. Drakenberg, K., Nikoshkov, A., Horváth, M.C., Fagergren, P., Gharibyan, A., Saarelainen, K., Rahman, S., Nylander, I., Bakalkin, G., Rajs, J., Keller, E., Hurd, Y.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Association of alcohol or other drug dependence with alleles of the mu opioid receptor gene (OPRM1). Kranzler, H.R., Gelernter, J., O'Malley, S., Hernandez-Avila, C.A., Kaufman, D. Alcohol. Clin. Exp. Res. (1998) [Pubmed]
  10. Endogenous opioid receptor genes and alcohol dependence among Taiwanese Han. Loh, e.l. .W., Fann, C.S., Chang, Y.T., Chang, C.J., Cheng, A.T. Alcohol. Clin. Exp. Res. (2004) [Pubmed]
  11. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Finn, A.K., Whistler, J.L. Neuron (2001) [Pubmed]
  12. Morphine induces terminal micro-opioid receptor desensitization by sustained phosphorylation of serine-375. Schulz, S., Mayer, D., Pfeiffer, M., Stumm, R., Koch, T., Höllt, V. EMBO J. (2004) [Pubmed]
  13. Association between two {micro}-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Zhang, H., Luo, X., Kranzler, H.R., Lappalainen, J., Yang, B.Z., Krupitsky, E., Zvartau, E., Gelernter, J. Hum. Mol. Genet. (2006) [Pubmed]
  14. Internalization and down-regulation of mu opioid receptors by endomorphins and morphine in SH-SY5Y human neuroblastoma cells. Horner, K.A., Zadina, J.E. Brain Res. (2004) [Pubmed]
  15. DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. Matsuzaki, S., Canis, M., Vaurs-Barrière, C., Pouly, J.L., Boespflug-Tanguy, O., Penault-Llorca, F., Dechelotte, P., Dastugue, B., Okamura, K., Mage, G. Mol. Hum. Reprod. (2004) [Pubmed]
  16. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hao, K., Wang, X., Niu, T., Xu, X., Li, A., Chang, W., Wang, L., Li, G., Laird, N., Xu, X. Hum. Mol. Genet. (2004) [Pubmed]
  17. Mu opioid receptor gene variants: lack of association with alcohol dependence. Bergen, A.W., Kokoszka, J., Peterson, R., Long, J.C., Virkkunen, M., Linnoila, M., Goldman, D. Mol. Psychiatry (1997) [Pubmed]
  18. ADP-ribosylation factor-dependent phospholipase D2 activation is required for agonist-induced mu-opioid receptor endocytosis. Koch, T., Brandenburg, L.O., Schulz, S., Liang, Y., Klein, J., Hollt, V. J. Biol. Chem. (2003) [Pubmed]
  19. Threonine 180 is required for G-protein-coupled receptor kinase 3- and beta-arrestin 2-mediated desensitization of the mu-opioid receptor in Xenopus oocytes. Celver, J.P., Lowe, J., Kovoor, A., Gurevich, V.V., Chavkin, C. J. Biol. Chem. (2001) [Pubmed]
  20. Functional reduction in mu-opioidergic system in the spinal cord under a neuropathic pain-like state following chronic ethanol consumption in the rat. Narita, M., Miyoshi, K., Narita, M., Suzuki, T. Neuroscience (2007) [Pubmed]
  21. Relationship of opioid receptors with GABAergic neurons in the rat inferior colliculus. Tongjaroenbuangam, W., Jongkamonwiwat, N., Phansuwan-Pujito, P., Casalotti, S.O., Forge, A., Dodson, H., Govitrapong, P. Eur. J. Neurosci. (2006) [Pubmed]
  22. Enkephalinergic afferents of the centromedial amygdala in the rat. Poulin, J.F., Chevalier, B., Laforest, S., Drolet, G. J. Comp. Neurol. (2006) [Pubmed]
  23. 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]
  24. Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Shi, J., Hui, L., Xu, Y., Wang, F., Huang, W., Hu, G. Hum. Mutat. (2002) [Pubmed]
  25. Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1). Wang, D., Sad??e, W. The AAPS journal [electronic resource]. (2006) [Pubmed]
  26. Poly(C) binding protein family is a transcription factor in mu-opioid receptor gene expression. Kim, S.S., Pandey, K.K., Choi, H.S., Kim, S.Y., Law, P.Y., Wei, L.N., Loh, H.H. Mol. Pharmacol. (2005) [Pubmed]
  27. Engineering and functional immobilization of opioid receptors. Ott, D., Neldner, Y., Cèbe, R., Dodevski, I., Plückthun, A. Protein Eng. Des. Sel. (2005) [Pubmed]
  28. 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]
  29. 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]
  30. Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders. Tanaka, S., Matsunaga, H., Kimura, M., Tatsumi, K., Hidaka, Y., Takano, T., Uema, T., Takeda, M., Amino, N. J. Neuroimmunol. (2003) [Pubmed]
  31. Association of micro-opioid receptor gene polymorphism A118G with alcohol dependence in a Japanese population. Nishizawa, D., Han, W., Hasegawa, J., Ishida, T., Numata, Y., Sato, T., Kawai, A., Ikeda, K. Neuropsychobiology (2006) [Pubmed]
  32. A genetic association study of the mu opioid receptor and severe opioid dependence. Crowley, J.J., Oslin, D.W., Patkar, A.A., Gottheil, E., DeMaria, P.A., O'Brien, C.P., Berrettini, W.H., Grice, D.E. Psychiatr. Genet. (2003) [Pubmed]
 
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