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The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor
Abstract
The most common single nucleotide polymorphism in the coding region of the human mu opioid receptor gene is the A118G variant, an adenine to guanine transition at nucleotide position 118 of the coding sequence of the gene. This polymorphism codes for an asparagine to aspartic acid substitution at amino acid 40 in the amino‐terminus, thereby removing a potential extracellular glycosylation site. Using in vitro cellular expression assays, this variant has been reported to change binding of the endogenous agonist beta‐endorphin and signaling of the receptor following binding of beta‐endorphin. Three clinical studies report that A118G genotype affects opioid antagonist‐mediated increases in cortisol levels. These studies demonstrate a functional role of this variant in responses to endogenous and exogenous opioids. To further characterize function, we expressed the prototype and variant receptors in two types of cells (human 293 embryonic kidney cells and Syrian hamster adenovirus‐12‐induced tumor cells). Stable expression of variant and prototype receptors was characterized by differences in levels of cell surface binding capacity (Bmax), forskolin‐induced cAMP accumulation, as well as agonist‐induced accumulation of cAMP (EC 50) for several agonists, but not for beta‐endorphin. In contrast, transiently expressed variant receptors showed only a minor difference in cell surface binding capacity compared to the prototype, and no differences in cAMP EC 50 values.
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“The A118G variant has enhanced binding and signaling properties, but low expression of mRNA (Zhang et al 2005; Kroslak et al 2007).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Kroslak et al 2007
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Bond, C. E., LaForge, K. S., Tian, M., Melia, D., Zhang, S., Borg, L., Gong, J., Schluger, J. H., Strong, J. A., Leal, S. M., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9608 · Cited by 1,072
Self-citationKreek, M. J., Nielsen, D. A., Butelman, E. R., & LaForge, K. S. (2005) · Nature Neuroscience · doi:10.1038/nn1583 · Cited by 1,024
Self-citationOslin, D. W., Berrettini, W., Kranzler, H. R., Pettinati, H., Gelernter, J., Volpicelli, J. R., & O'Brien, C. P. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300219 · Cited by 571
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. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504942200 · Cited by 563
Sinha, R., Garcia, M., Paliwal, P., Kreek, M. J., & Rounsaville, B. J. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.3.324 · Cited by 528
Self-citationPharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments
Kreek, M. J., Bart, G., Lilly, C., Laforge, K. S., & Nielsen, D. A. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.1.1 · Cited by 391
Self-citationKreek, M. J., LaForge, K. S., & Butelman, E. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd897 · Cited by 371
Self-citationHoehe, M. R. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.19.2895 · Cited by 288
μ opioid receptor gene variants: lack of association with alcohol dependence
Bergen, A. W., Kokoszka, J., Peterson, R. J., Long, J. C., Virkkunen, M. E., Linnoila, M., & Goldman, D. A. (1997) · Molecular Psychiatry · doi:10.1038/sj.mp.4000331 · Cited by 271
Beyer, A., Koch, T., Schröder, H., Schulz, S., & Höllt, V. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02340.x · Cited by 258
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Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., Koch, T., Evans, C. J., & Christie, M. J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.005942 · Cited by 802
“However, the initial report of this variant affecting b-endorphin potency has not been replicated (Beyer et al., 2004; Kroslak et al., 2007).”
BackgroundMu Opioids and Their Receptors: Evolution of a Concept
Pasternak, G. W., & Pan, Y. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007138 · Cited by 582
“, 2008), and the A118G mutation altering glycosylation has been implicated in addiction (Bart et al., 2005; Kreek and LaForge, 2007; Kroslak et al., 2007).”
BackgroundInfluentialOpioid receptors: drivers to addiction?
Darcq, E., & Kieffer, B. L. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0028-x · Cited by 365
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“The rarer G118 allele has shown greater affinity for β-endorphin and morphine, but reduced mRNA and protein expression in vitro (22).”
BackgroundBurkett, J. P., & Young, L. J. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2794-x · Cited by 307
“The A118G variant has enhanced binding and signaling properties, but low expression of mRNA (Zhang et al. 2005; Kroslak et al. 2007).”
The Interpersonal Dimension of Borderline Personality Disorder: Toward a Neuropeptide Model
Stanley, B., & Siever, L. J. (2009) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09050744 · Cited by 301
“endorphin in vitro (47, 82) and gain of function in vivo (83, 84), as exemplified in increased alcohol-induced stimulation, an in vivo behavior mediated by endogenous opioids.”
BackgroundWay, B. M., Taylor, S. E., & Eisenberger, N. I. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812612106 · Cited by 264
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Heilig, M. A., Goldman, D. A., Berrettini, W. H., & O’Brien, C. P. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3110 · Cited by 256
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Kreek, M. J., Levran, O., Reed, B., Schlussman, S. D., Zhou, Y., & Butelman, E. R. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60390 · Cited by 220
“This change results in removal of an N-glycosylation site in extracellular domain, which in turn results in a higher affinity binding of β -EP than the prototype, altered receptor-binding site availability, and signaling efficacy as well as reduced mRNA levels (85–89).”
Self-citationMeta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment
Walter, C., & Lötsch, J. (2009) · Pain · doi:10.1016/j.pain.2009.07.013 · Cited by 200
“However, the underlying molecular assumptions of increased endorphin binding [4] or decreased efficiency of exogenous opioids [31] at the variant N40D l-opioid receptors have to acknowledge their non-reproduction at the molecular level [3,20].”
BackgroundThe genetics of addiction—a translational perspective
Arpana Agrawal, A., Verweij, K. J. H., Gillespie, N. A., Heath, A. C., Lessov‐Schlaggar, C. N., Martin, N. G., Nelson, E. C., Slutske, W. S., Whitfield, J. B., & Lynskey, M. T. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.54 · Cited by 202
Variation at the mu-opioid receptor gene ( OPRM1 ) influences attachment behavior in infant primates
Barr, C. S., Schwandt, M. L., Lindell, S. G., Higley, J. D., Maestripieri, D., Goldman, D., Suomi, S. J., & Heilig, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710225105 · Cited by 191
“Although the exact mechanism remains unclear (16, 17), in vivo data support a gain-of-function role for these variants, as shown, for example, by increased alcohol-induced stimulation, an effect”
BackgroundEndogenous opioid system dysregulation in depression: implications for new therapeutic approaches
Peciña, M., Karp, J. F., Mathew, S. J., Todtenkopf, M. S., Ehrich, E. W., & Zubieta, J.-K. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0117-2 · Cited by 197
“Animal studies have suggested that the G118 allele is associated with loss of function of the receptor, lower surface receptor expression, decreased forskolin-induced cAMP activation, and lower agonistinduced MOPR activation [84, 85].”
Peciña, M., Love, T., Stohler, C. S., Goldman, D. A., & Zubieta, J.-K. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.272 · Cited by 161
“All rights reserved 0893-133X/15 www.neuropsychopharmacology.org reduction in protein levels in CHO cells expressing the G118 variant; Kroslak et al (2007) also demonstrated that cell culture systems expressing the G118 allele had lower surface receptor expression, decreased forskolin-induced cAMP…”
Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior
Mague, S. D., Isiegas, C., Huang, P., Liu‐Chen, L., Lerman, C. E., & Blendy, J. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901800106 · Cited by 160
“More recent data support this claim, showing lower surface receptor expression, decreased forskolin-induced cAMP activation, and lower agonist-induced MOPR activation in cell culture systems expressing the G118 allele (20).”
BackgroundResultOPRM1 A118G Gene Variant and Postoperative Opioid Requirement
Hwang, I. C., Park, J. Y., Myung, S., Ahn, H. Y., Fukuda, K., & Liao, Q. (2014) · Anesthesiology · doi:10.1097/aln.0000000000000405 · Cited by 152
“, duration of opioid efficacy or numerical rating score) were included; and (5) the human 118A>G variant was not included, or no data were reported for this variant.”
BackgroundOertel, B. G., Kettner, M., Scholich, K., Renné, C., Roskam, B., Geißlinger, G., Schmidt, P. H., & Lötsch, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807030200 · Cited by 149
Landau, R., Kern, C., Columb, M. O., Smiley, R. M., & Blouin, J. (2008) · Pain · doi:10.1016/j.pain.2008.02.023 · Cited by 147
“[4], this was not the case in their study for smaller endogenous opioid peptides or l-preferring opioid agonists, or for the opioid antagonist, naloxone, nor was this finding replicated by others [2,3] or by the same group recently [26].”
The genetics of the opioid system and specific drug addictions
Levran, O., Yuferov, V. P., & Kreek, M. J. (2012) · Human Genetics · doi:10.1007/s00439-012-1172-4 · Cited by 147
Self-citationHayashida, M., Nagashima, M., Satoh, Y., Katoh, R., Tagami, M., Ide, S., Kasai, S., Nishizawa, D., Ogai, Y., Hasegawa, J., et al. (2008) · Pharmacogenomics · doi:10.2217/14622416.9.11.1605 · Cited by 141
OPRM1 SNP (A118G): Involvement in disease development, treatment response, and animal models
Mague, S. D., & Blendy, J. A. (2010) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2009.12.016 · Cited by 138
“Further evidence for a decrease in MOPR expression was demonstrated by studies showing a reduction in Bmax, indicative of a lower receptor number, following [3H]-DAMGO binding using both transient and stable expression of MOPR in AV-12 and HEK293 cells (Kroslak et al., 2007).”
BackgroundFukuda, K., Hayashida, M., Ide, S., Saita, N., Kokita, Y., Kasai, S., Nishizawa, D., Ogai, Y., Hasegawa, J., Nagashima, M., et al. (2009) · Pain · doi:10.1016/j.pain.2009.09.004 · Cited by 135
Tan, E.-C., Lim, E. C., Teo, Y.-Y., Lim, Y., Law, H.-Y., & Sia, A. T. (2009) · Molecular Pain · doi:10.1186/1744-8069-5-32 · Cited by 133
“Recent studies suggest that there is no difference between the two proteins in terms of binding affinity, sensitization, internalization or desensitization, but in vitro studies show that the there is lower expression of the receptor protein corresponding to the 118G allele [26-28].”
BackgroundGenetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence
Mistry, C. J., Bawor, M., Desai, D., Marsh, D. C., & Samaan, Z. (2014) · Current Psychiatry Reviews · doi:10.2174/1573400510666140320000928 · Cited by 136
“Using different methods, a study by Kroslak et al [71] found no changes in β-endorphin signaling at the rs1799971 µ receptor, and also determined that the binding affinities for exogenous agonists (morphine, methadone, and DAMGO) were not different.”
BackgroundMethodInfluentialA review of opioid addiction genetics
Crist, R. C., Reiner, B. C., & Berrettini, W. H. (2018) · Current Opinion in Psychology · doi:10.1016/j.copsyc.2018.07.014 · Cited by 131
Deumens, R., Steyaert, A., Forget, P., Schubert, M., Lavand'homme, P. M., Hermans, E., & Kock, M. D. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.01.002 · Cited by 126
Troisi, A., Frazzetto, G., Carola, V., Di Lorenzo, G., Coviello, M., D'Amato, F. R., Moles, A., Siracusano, A., & Gross, C. (2011) · Social Neuroscience · doi:10.1080/17470919.2010.482786 · Cited by 118
“The A118G variant of the OPRM1 is located in the coding region of the first exon and is the single nucleotide polymorphism (SNP) with the highest overall allelic frequency of any OPRM1 coding region variant reported, although its heterozygosity varies widely across populations (Kroslak et al., 2007).”
BackgroundTissue-Specific Glycosylation at the Glycopeptide Level
Medzihradszky, K. F., Kaasik, K., & Chalkley, R. J. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.050393 · Cited by 118
μ opioid receptor, social behaviour and autism spectrum disorder: reward matters
Pellissier, L. P., Gandía, J., Laboute, T., Becker, J. A. J., & Merrer, J. L. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13808 · Cited by 115
“Whereas six other rare polymorphisms exist, the A118G polymorphism of the OPRM1 gene (coding for the μ opioid receptor), removing a potential extracellular N-glycosylation site, is commonly found in European and Asian populations (15–60%) and considered as a gain-of-function in vitro and in vivo (Kroslak et al., 2007;…”
BackgroundHuang, P., Chen, C., Mague, S. D., Blendy, J. A., & Liu‐Chen, L. (2011) · Biochemical Journal · doi:10.1042/bj20111050 · Cited by 117
Crist, R. C., & Berrettini, W. H. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.10.018 · Cited by 115
“Decreased accumulation of the second-messenger cAMP transfected cells was observed in the presence of morphine, methadone, and DAMGO (Kroslak et al., 2007).”
InfluentialYuferov, V. P., Levran, O., Proudnikov, D., Nielsen, D. A., & Kreek, M. J. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05275.x · Cited by 106
Self-citationConsequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?
Mura, E., Govoni, S. M., Racchi, M., Carossa, Ranzani, G. N., Allegri, M., & van Schaik, A. (2013) · Journal of Pain Research · doi:10.2147/jpr.s42040 · Cited by 105
“Moreover, a lower cell-surface receptor binding site availability (B max ) (measured with [(3)H]-DAMGO) was observed in both HEK293 and AV-12 cell lines stably expressing the 118G variant compared with cells expressing the 118A receptor.(19,21) These effects on the expression of OPRM1 are particularly interesting.”
BackgroundDeb, I., Chakraborty, J., Gangopadhyay, P. K., Choudhury, S. R., & Das, S. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06472.x · Cited by 105
“Interestingly, unlike in human embryonic kidney cells (HEK293), the G allele increases binding affinity of OPRM1 for DAMGO in AV-12 cells (Kroslak et al. 2007), or protein levels of OPRM1 in Chinese Hamster Ovary cells (Zhang et al. 2005).”
BackgroundInfluentialNeuropathic and chronic pain stimuli downregulate central μ -opioid and dopaminergic transmission
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Self-citationThe opioid system in depression
Jelen, L. A., Stone, J. M., Young, A. H., & Mehta, M. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104800 · Cited by 108
“Several studies have explored the impact of MOR genetic variations on social behaviours and depressive symptoms with a focus on the A118G single nucleotide polymorphism (SNP) in the MOR (OPRM1) gene, where G allele status has been associated with loss of receptor function (Zhang et al., 2005; Kroslak et al., 2007).”
Epigenetic Variation in the Mu-Opioid Receptor Gene in Infants with Neonatal Abstinence Syndrome
Wachman, E. M., Hayes, M. J., Lester, B. M., Terrin, N. C., Brown, M. S., Nielsen, D. A., & Davis, J. M. (2014) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2014.05.040 · Cited by 100
“The common 118A>G rs1799971 SNP causes to an amino acid change resulting in a 3-fold increase in the binding affinity of the receptor with b-endorphin, altering the function of the hypothalamic-pituitary-adrenal axis, and vulnerability to addiction.(26,27) Data from animal models and in vivo studies indicate that the…”
BackgroundSelf-citationBruehl, S., Burns, J. W., Chung, O. Y., & Chont, M. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.12.003 · Cited by 88
“…the variant G allele does not influence exogenous opioid receptor binding (Bond et al., 1998), it is associated with reduced receptor expression (Kroslak et al., 2007; Zhang et al., 2005) and increased exogenous opioid analgesic requirements (Chou et al., 2006; Klepstad et al., 2004; Lotsch et…”
BackgroundCommon single nucleotide variants underlying drug addiction: more than a decade of research
Bühler, K., Giné, E., Echeverry‐Alzate, V., Calleja‐Conde, J., de Fonseca, F. R., & López‐Moreno, J. A. (2015) · Addiction Biology · doi:10.1111/adb.12204 · Cited by 96
“the highest overall frequency of any reported OPRM1 coding variant (Bond et al. 1998; Kroslak et al. 2007).”
BackgroundInfluentialThe evolution of vertebrate opioid receptors
Craig, W. S. (2009) · Frontiers in bioscience · doi:10.2741/3306 · Cited by 90
Patriquin, M. A., Bauer, I. E., Soares, J. C., Graham, D. P., & Nielsen, D. A. (2015) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000095 · Cited by 89
“Studies have demonstrated that the 118G allele codes for a receptor that is expressed at lower levels (Wand et al., 2002; Zhang et al., 2005; Kroslak et al., 2007) but binds β-endorphins with a higher affinity (Bond et al., 1998).”
Self-citationRay, L. A., Barr, C. S., Blendy, J. A., Oslin, D. W., Goldman, D. A., & Anton, R. F. (2011) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01633.x · Cited by 81
Burns, J. A., Kroll, D. S., Feldman, D. E., Liu, C. K., Manza, P., Wiers, C. E., Volkow, N. D., & Wang, G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00626 · Cited by 75
“One proposed mechanism suggests that the amino acid substitution removes an extracellular glycosylation site, potentially interfering with the protein’s folding or incorporation into the cell membrane (101).”
BackgroundHancock, D. B., Levy, J. L., Gaddis, N., Glasheen, C., Saccone, N. L., Page, G. P., Hulse, G. K., Wildenauer, D., Kelty, E. A., Schwab, S. G., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.01.003 · Cited by 71
Nielsen, L. M., Olesen, A. E., Branford, R., Christrup, L. L., Sato, H., & Drewes, A. M. (2014) · Pain Practice · doi:10.1111/papr.12232 · Cited by 70
Higham, J. P., Barr, C. S., Hoffman, C. L., Mandalaywala, T. M., Parker, K. J., & Maestripieri, D. (2011) · Behavioral Neuroscience · doi:10.1037/a0022695 · Cited by 69
“The G allele for this gene causes an amino acid substitution in the N-terminal arm of the receptor, which was originally reported to increase their affinity for -endorphin (Bond et al., 1998), although this effect may be cell-line dependent (Kroslak et al., 2007).”
Current evidence for a modulation of low back pain by human genetic variants
Tegeder, I., & Lötsch, J. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00703.x · Cited by 69
“This fits to neither of the above-mentioned molecular mechanisms and is best explained with an earlier molecular finding of increased binding affinity of -endorphin at the variant -opioid receptors [103], which, however, had not been reproduced [104, 105].”
ResultPharmacogenetic Treatments for Drug Addiction: Alcohol and Opiates
Haile, C. N., Kosten, T. A., & Kosten, T. R. (2008) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990802122564 · Cited by 73
“A number of in vitro cell assay studies (11, 14, 86) and post-mortem analysis of A118G mRNA transcript levels (174) further indicate that the A118G SNP results in decreased mu-receptor protein levels and likely compromised receptor function.”
BackgroundResultInfluentialHermann, D., Hirth, N., Reimold, M., Batra, A., Smolka, M. N., Hoffmann, S., Kiefer, F., Noori, H. R., Sommer, W. H., Reischl, G., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.145 · Cited by 64
“However, our findings seem contradictory with other publications showing decreased MOR expression (in vitro cell culture study by Kroslak et al. (2007); human autopsy brain tissue analyses of MOR mRNA and protein, N= 76 AA, N= 8 AG and N= 3 GG OPRM1 genotype by Zhang et al., (2005)) and a reduced…”
ResultRecent Developments in the Study of Opioid Receptors
Cox, B. M. (2012) · Molecular Pharmacology · doi:10.1124/mol.112.083279 · Cited by 64
“Kroslak et al. (2007) reported that 118G reduced the level of MOPr protein (observed as reduced ligand Bmax for opioid ligands) and found a lower potency of opiates as inhibitors of adenylyl cyclase in oocytes transfected with this receptor variant.”
BackgroundMahmoud, S., Thorsell, A., Sommer, W. H., Heilig, M. A., Holgate, J. K., Bartlett, S. E., & Ruiz-Velasco, V. (2011) · Anesthesiology · doi:10.1097/aln.0b013e318231fc11 · Cited by 62
Zhang, Y., Picetti, R., Butelman, E. R., Ho, A., Blendy, J. A., & Kreek, M. J. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.286 · Cited by 61
“…SNP, resulting in increased affinity and potency of the endogenous neuropeptide -endorphin at MOPR (although this was not observed across all studies and methodologies), and reducing [3H] DAMGO (ie, MOPR) maximum binding (Bmax) in vitro (Bond et al, 1998; Zhang et al, 2005; Kroslak et al, 2007).”
BackgroundSelf-citationPharmacogenomics of the Human µ-Opioid Receptor
Kasai, S., & Ikeda, K. (2011) · Pharmacogenomics · doi:10.2217/pgs.11.68 · Cited by 61
Hao, Y., Huang, W., Nielsen, D. A., & Kosten, T. A. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00021 · Cited by 66
“The G allele of the OPRM1 gene is associated with reduced levels of mu-opioid receptor mRNA and protein compared to the A allele (Kroslak et al., 2007).”
BackgroundSelf-citationZhou, Y., Proudnikov, D., Yuferov, V., & Kreek, M. J. (2010) · Brain Research · doi:10.1016/j.brainres.2009.11.015 · Cited by 58
“Therefore we studied this in subsequent work, and showed that, indeed, in three different cell types, there is much lower cell-surface presentation of the A118G variant receptor than the prototype (Kroslak et al., 2007).”
Self-citationBilbao, A., Robinson, J. E., Heilig, M. A., Malanga, C. J., Spanagel, R., Sommer, W. H., & Thorsell, A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.08.021 · Cited by 59
Sia, A. T. H., Lim, Y., Lim, E. C. P., Ocampo, C. E., Lim, W.-Y., Cheong, P., & Tan, E. (2013) · Journal of Pain · doi:10.1016/j.jpain.2013.03.008 · Cited by 58
Pharmacogenomic considerations in opioid analgesia
Landau, R. (2012) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s23422 · Cited by 57
“In vitro studies have suggested that A118G polymorphism affects receptor binding characteristics 114,115 or messenger RNA expression levels; 116 however, under some experimental conditions, there was no effect on function 117 or expression levels.”
Common and specific liability to addiction: Approaches to association studies of opioid addiction
Nielsen, D. A., & Kreek, M. J. (2012) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2012.03.026 · Cited by 55
“In stable transfected cell lines, the expression of the variant receptor showed lower forskolin-induced cAMP accumulation and lower receptor binding site availability (Kroslak et al., 2007).”
BackgroundSelf-citationThe Role of Hydromorphone and OPRM1 in Postoperative Pain Relief with Hydrocodone
Jortani, S. A. (2013) · Pain Physician · doi:10.36076/ppj.2013/16/e227 · Cited by 55
Wu, W. D., Wang, Y., Fang, Y., & Zhou, H. (2009) · Molecular Diagnosis & Therapy · doi:10.1007/bf03256337 · Cited by 55
“Our results showing fentanyl to be less effective as an analgesic in surgical patients with the OPRM1 118G allele agree with the findings of others that the G allele increases morphine requirements for cancer and total knee arthroplasty pain,([12,24]) and for post-cesarean analgesia and after hysterectomy and major ab…”
ResultLovallo, W. R., Enoch, M., Acheson, A., Cohoon, A. J., Sorocco, K. H., Hodgkinson, C. A., Vincent, A. S., Glahn, D. C., & Goldman, D. A. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.101 · Cited by 54
“All rights reserved 0893-133X/15 www.neuropsychopharmacology.org mu-opioid receptor binding relative to the more common A118 allele (Bond et al, 1998), although studies using human receptors have not observed this difference (Beyer et al, 2004; Kroslak et al, 2007; Zhang et al, 2005).”
Xu, J., Lu, Z., Xu, M., Pan, L., Deng, Y., Xie, X., Liu, H., Ding, S., Hurd, Y. L., Pasternak, G. W., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3986-13.2014 · Cited by 55
“For example, A118G increases the affinity of MOR-1 for -endorphin (Bond et al., 1998; Kroslak et al., 2007), and lowers expression of MOR-1 mRNA and protein likely via altering an mRNA secondary structure (Zhang et al., 2005), or reducing the N-glycosylation and protein stability of MOR-1 (Huang et…”
BackgroundWasilewski, A., Lewandowska, U., Mosińska, P., Watała, C. W., Storr, M., Fichna, J., & Venkatesan, T. (2017) · The American Journal of Gastroenterology · doi:10.1038/ajg.2017.73 · Cited by 55
Opiates, overeating and obesity: a psychogenetic analysis
Davis, C. A., Zai, C. C. H., Levitan, R. D., Kaplan, A. S., Carter, J. C., Reid‐Westoby, C., Curtis, C., Wight, K., & Kennedy, J. L. (2011) · International Journal of Obesity · doi:10.1038/ijo.2010.276 · Cited by 51
Child μ-Opioid Receptor Gene Variant Influences Parent–Child Relations
Copeland, W., Sun, H., Costello, E. J., Angold, A. C., Heilig, M. A., & Barr, C. S. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.251 · Cited by 53
“…reserved 0893-133X/11 $32.00 www.neuropsychopharmacology.org Originally considered a gain-of-function allele (Bond et al, 1998), recent studies examining either in vitro properties or genetic association with substance disorders have produced mixed results (Arias et al, 2006; Kroslak et al, 2007).”
InfluentialEndogenous opiates and behavior: 2007
Bodnar, R. J. (2008) · Peptides · doi:10.1016/j.peptides.2008.09.007 · Cited by 54
“Analyzing the evolution of BEND post-translational processing events by studying reptiles revealed that the amino acid substitutions that eliminated the post-translational process in reptilian-related tetrapods occurred in ancestral amniotes [1145].”
BackgroundInfluentialChidambaran, V., Mavi, J., Esslinger, H. R., Pilipenko, V. V., Martin, L. J., Zhang, K., & Sadhasivam, S. (2014) · The Pharmacogenomics Journal · doi:10.1038/tpj.2014.59 · Cited by 47
Mechanisms of the placebo effect in pain and psychiatric disorders
Holmes, R. D., Tiwari, A. K., & Kennedy, J. L. (2016) · The Pharmacogenomics Journal · doi:10.1038/tpj.2016.15 · Cited by 49
Reed, B., Butelman, E. R., Yuferov, V. P., Randesi, M., & Kreek, M. J. (2014) · Current Psychiatry Reports · doi:10.1007/s11920-014-0504-6 · Cited by 51
Self-citationDomino, E. F., Evans, C., Ni, L., Guthrie, S. K., Koeppe, R. A., & Zubieta, J. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.04.003 · Cited by 43
“Kroslak et al. (2007) have emphasized the most frequent coding variant of the human mu opioid receptor is the adenine to guanine transition A118G.”
Immune Response Activation and Immunomodulation
Tyagi, R. K., & Bisen, P. S. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.73708 · Cited by 44
Analgesia and central side‐effects: two separate dimensions of morphine response
Droney, J., Gretton, S. K., Sato, H., Ross, J. R., Branford, R., Welsh, K. I., Cookson, W., & Riley, J. L. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12008 · Cited by 40
Bailey, A., Metaxas, A., Al‐Hasani, R., Keyworth, H. L., Forster, D. M., & Kitchen, I. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07104.x · Cited by 40
“This is in complete agreement with Bond et al. (1998) and Kroslak et al. (2007), who showed that A118G human variant of MOP-r, which has been associated with opioid addiction (LaForge et al., 2000), has significantly higher affinity and potency to activate G-protein-coupled inward rectifying…”
MethodResultAddiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons
Halikere, A., Popova, D., Scarnati, M. S., Hamod, A., Swerdel, M. R., Moore, J. C., Tischfield, J. A., Hart, R. P., & Pang, Z. P. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0507-0 · Cited by 37
“There have been numerous investigations into the functional consequences of the MOR D40 variant on receptor activation in overexpression models or knock-in models with mouse, primates, and humans 6, 8–16 .”
Hartwell, E. E., Feinn, R., Morris, P. E., Gelernter, J. E., Krystal, J. H., Arias, A. J., Hoffman, M., Petrakis, I. L., Gueorguieva, R. V., Schacht, J. P., et al. (2020) · Addiction · doi:10.1111/add.14975 · Cited by 41
“The mu-opioid receptor encoded by the Asp40 allele has been shown to bind ß-endorphin and activate G-protein coupled potassium ion channels more than the receptor encoded by the Asn40 allele [13], though subsequent studies have also shown loss-of-function effects of the Asp40 allele [14].”
BackgroundClarke, T., Crist, R. C., Kampman, K. M., Dackis, C. A., Pettinati, H. M., O’Brien, C. P., Oslin, D. W., Ferraro, T. N., Lohoff, F. W., & Berrettini, W. H. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.02.018 · Cited by 40
“Functional studies have found differential expression, receptor binding, signaling efficiency, and altered intracellular effects to be associated with this variant [9, 14, 22, 29, 41].”
BackgroundSchwandt, M. L., Lindell, S. G., Higley, J. D., Suomi, S. J., Heilig, M. A., & Barr, C. S. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.03.002 · Cited by 37
“Although the precise molecular mechanism remains unclear (Befort et al., 2001; Beyer et al., 2004; Kroslak, 2007), it is well established that the A118G variant has functional consequences in vivo.”
Woodcock, E. A., Lundahl, L. H., Burmeister, M., & Greenwald, M. K. (2015) · American Journal on Addictions · doi:10.1111/ajad.12187 · Cited by 38
“andKroslak et al.(19) each found human (118)G-variant cell lines demonstrated lower cell-surface MOR agonist binding capacity (lower Bmax).”
Ducat, E. A., Ray, B. M., Bart, G. B., Umemura, Y., Varon, J., Ho, A., & Kreek, M. J. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2011.00313.x · Cited by 37
“…activation of G-protein-coupled potassium channels; (b) and increased receptor-binding affinity for beta-endorphin, but not for the other endogenous or exogenous opioid ligands; and (c) a reduced expression of the mu-opioid receptor on cell surfaces (Bond et al. 1998; Kroslak et al. 2007).”
BackgroundSelf-citationWalter, C., Doehring, A., Oertel, B. G., & Lötsch, J. (2013) · Pharmacogenomics · doi:10.2217/pgs.13.187 · Cited by 36
Hirasawa-Fujita, M., Bly, M. J., Ellingrod, V. L., Dalack, G. W., & Domino, E. F. (2017) · Clinical Schizophrenia & Related Psychoses · doi:10.3371/1935-1232-11.1.39 · Cited by 36
Variable response to opioid treatment: any genetic predictors within sight?
Skorpen, F., Laugsand, E., Klepstad, P., & Kaasa, S. (2008) · Palliative Medicine · doi:10.1177/0269216308089302 · Cited by 35
Alcohol: A stimulant activating brain stress responsive systems with persistent neuroadaptation
Zhou, Y., & Kreek, M. J. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.05.044 · Cited by 34
“This change results in removal of an N-glycosylation site in the extracellular domain, which in turn results in altered receptor binding site availability, reduced mRNA levels, high affinity binding of bendorphin and altered signaling efficacy (Bond et al., 1998; Beyer et al., 2004; Kroslak et al., 2007; Zhang et al.,…”
BackgroundSelf-citationA118G Polymorphism of OPRM1 Gene is Associated with Schizophrenia
Šerý, O., Přikryl, R., Častulík, L., & Šťastný, F. (2010) · Journal of Molecular Neuroscience · doi:10.1007/s12031-010-9327-z · Cited by 33
“…leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at amino acid position 40, reduces through changed receptor glycosylation the affinity for endogenous opioids (Kroslak et al. 2007), which may be related to a developmental myelination disorder in individuals with schizophrenia.”
BackgroundPharmacogenomics for personalized pain medicine
Ko, T., Wong, C., Wu, J.-Y., & Chen, Y.-T. (2016) · Acta anaesthesiologica Taiwanica · doi:10.1016/j.aat.2016.02.001 · Cited by 32
Are Opioids Effective in Relieving Neuropathic Pain?
Schembri, E. (2018) · SN Comprehensive Clinical Medicine · doi:10.1007/s42399-018-0009-4 · Cited by 37
“This causes an exchange of asparagine to aspartate at the site of amino acid 40, leading to reduced signaling efficacy and possibly reduced OPRM1 expression [103].”
BackgroundPharmacogenetics of Addiction Therapy
Nielsen, D. A., Nielsen, E. M., Dasari, T., & Spellicy, C. J. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-0956-8_15 · Cited by 32
Self-citationPlacebo effects and the molecular biological components involved
Cai, L., & He, L. (2019) · General Psychiatry · doi:10.1136/gpsych-2019-100089 · Cited by 33
Carbamidomethylation Side Reactions May Lead to Glycan Misassignments in Glycopeptide Analysis
Darula, Z., & Medzihradszky, K. F. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b01121 · Cited by 31
Knapman, A., Santiago, M., & Connor, M. A. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12785 · Cited by 29
“Subsequent studies have found no differences in β-endorphin potency between N40D- and wildtype (WT)-MOP receptors (Befort et al., 2001; Beyer et al., 2004; Kroslak et al., 2007).”
BackgroundResultLötsch, J., & Ultsch, A. (2013) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2013.07.010 · Cited by 29
“Moreover, the variant is well known to reduce opioid receptor signaling efficiency [52] and expression [53–55], including a genetic–epigenetic interaction impeding receptor upregulation [56].”
BackgroundNicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms
Nuechterlein, E. B., Ni, L., Domino, E. F., & Zubieta, J. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.04.006 · Cited by 28
Bidirectional translational research: Progress in understanding addictive diseases
Kreek, M. J., Schlussman, S. D., Reed, B., Zhang, Y., Nielsen, D. A., Levran, O., Zhou, Y., & Butelman, E. R. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.07.042 · Cited by 28
“It has also been reported that the A118G allele expresses approximately one-half the OPRM1 mRNA and about one-tenth the mu-opioid receptor protein (Beyer et al., 2004; Zhang, Wang, et al., 2005; Kroslak et al., 2007).”
BackgroundSelf-citationRobinson, J. E., Vardy, E., DiBerto, J. F., Chefer, V. I., White, K. L., Fish, E. W., Chen, M., Gigante, E. D., Krouse, M. C., Sun, H., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.109 · Cited by 28
“Several in vitro, animal, and human studies suggest that MOR expression is decreased by the OPRM1 A118G polymorphism (Beyer et al, 2004; Kroslak et al, 2007; Mague et al, 2009; Pecina et al, 2015; Ray et al, 2011; Wang et al, 2012; Weerts et al, 2013).”
BackgroundLee, M. R., Gallen, C. L., Zhang, X., Hodgkinson, C. A., Goldman, D., Stein, E. A., & Barr, C. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024203 · Cited by 27
Association study of OPRM1 polymorphisms with Schizophrenia in Han Chinese population
Ding, S., Chen, B., Zheng, Y., Lu, Q., Liu, L., & Zhuge, Q. C. (2013) · BMC Psychiatry · doi:10.1186/1471-244x-13-107 · Cited by 27
“This polymorphism, leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at amino acid position 40, reduces through changed receptor glycosylation the affinity for endogenous opioids [20].”
BackgroundPharmacogenetics of Methadone Response
Fonseca, F., & Torrens, M. (2017) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-017-0311-y · Cited by 26
“Carriers of this variant have reduced agonist-induced receptor signalling efficacy as shown in the post-mortem brain [44], differences in signal response to agonists [45], and stronger cortisol response to receptor blockade by naloxone, with a reduced agonist effect of morphine-6-glucuronide [46].”
BackgroundCapraris, A. D., Cinnella, G., Marolla, A., Salatto, P., Lima, S. D., Vetuschi, P., Consoletti, L., Gesualdo, L., & DAMBROSIO, M. (2011) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463201102400417 · Cited by 26
Metadata
- Authors
- Kroslak, T., LaForge, K. S., Gianotti, R. J., Ho, A., Nielsen, D. A., & Kreek, M. J.
- Affiliations
- Rockefeller University (US)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2007-06-03
- Volume
- 103
- Issue
- 1
- Pages
- 77-87
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2039877085
- Cited by
- 213
- References
- 42
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 9 · 2019: 8 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 16 · 2014: 21 · 2013: 17 · 2012: 23
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (C17893)
- National Institute on Drug Abuse (R01DA012848, P60 DA 05130, P60DA005130, R01-DA-12848)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- mu-opioid receptor, A118G polymorphism, single nucleotide polymorphisms, cAMP signaling, forskolin, cell surface binding
- MeSH terms
- Cyclic AMP, Analgesics, Opioid, Animals, Binding, Competitive, Cell Line, Cell Membrane, Dose-Response Relationship, Drug, Fibroblasts, Colforsin, Cricetinae, Humans, Kidney, Mesocricetus, Receptors, Opioid, mu, Gene Transfer Techniques, Polymorphism, Single Nucleotide, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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