Abstract
The human μ-opioid receptor gene (OPRM1), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies. The μ-opioid receptor (MOR), encoded by OPRM1, contributes to regulate the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic polymorphisms of opioid receptors are candidates for the variability of clinical opioid effects. The non-synonymous polymorphism A118G of the OPRM1 has been repeatedly associated with the efficacy of opioid treatments for pain and various types of dependence. Genetic analysis of human opioid receptors has evidenced the presence of numerous polymorphisms either in exonic or in intronic sequences as well as the presence of synonymous coding variants that may have important effects on transcription, mRNA stability, and splicing, thus affecting gene function despite not directly disrupting any specific residue. Genotyping of opioid receptors is still in its infancy and a relevant progress in this field can be achieved by using advanced gene sequencing techniques described in this review that allow the researchers to obtain vast quantities of data on human genomes and transcriptomes in a brief period of time and with affordable costs.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Pasternak GW, Pan YX (2013) Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 65:1257–1317
Cox BM (2013) Recent developments in the study of opioid receptors. Mol Pharmacol 83:723–728
Butelman ER, Yuferov V, Kreek MJ (2012) Kappa opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci 35:587–596
Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363–1381
Stockton SD Jr, Devi LA (2012) Functional relevance of mu-delta opioid receptor heteromerization: a role in novel signaling and implications for the treatment of addiction disorders: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend 121:167–172
Crist RC, Berrettini WH (2013) Pharmacogenetics of OPRM1. Pharmacol Biochem Behav. doi:10.1016/j.pbb.2013.10.018
Manglik A, Kruse AC, Kobilka TS et al (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485:321–326
Lötsch J, Stuck B, Hummel T (2006) The human mu-opioid receptor gene polymorphism 118A > G decreases cortical activation in response to specific nociceptive stimulation. Behav Neurosci 120:1218–1224
Holliday KL, Nicholl BI, Macfarlane GJ et al (2009) Do genetic predictors of pain sensitivity associate with persistent widespread pain? Mol Pain 5:56
Anderson KO, Green CR, Payne R (2009) Racial and ethnic disparities in pain: causes and consequences of unequal care. J Pain 10:1187–1204
Green CR, Anderson KO, Baker TA et al (2003) The unequal burden of pain: confronting racial and ethnic disparities in pain. Pain Med 4:277–294
Plesh O, Adams SH, Gansky SA (2011) Racial/ethnic and gender prevalences in reported common pains in a national sample. J Orofac Pain 25:25–31
Green CR, Wheeler JR (2003) Physician variability in the management of acute postoperative and cancer pain: a quantitative analysis of the Michigan experience. Pain Med 4:8–20
Green CR, Baker TA, Sato Y et al (2003) Race and chronic pain: a comprehensive study of young black and white Americans presenting for management. J Pain 4:176–183
Green CR, Ndao-Brumblay SK, Nagrant AM et al (2004) Race, age, and gender influences among clusters of African American and white patients with chronic pain. J Pain 5:171–182
Campbell CM, Edwards RR, Fillingim RB (2005) Ethnic differences in responses to multiple experimental pain stimuli. Pain 113:20–26
Forsythe LP, Thorn B, Day M et al (2011) Race and sex differences in primary appraisals, catastrophizing, and experimental pain outcomes. J Pain 12:563–572
Jimenez N, Seidel K, Martin LD et al (2010) Perioperative analgesic treatment in Latino and non-Latino pediatric patients. J Health Care Poor Underserved 21:229–236
Fukuda K, Hayashida M, Ikeda K et al (2010) Diversity of opioid requirements for postoperative pain control following oral surgery—is it affected by polymorphism of the mu-opioid receptor? Anesth Prog 57:145–149
Bond C, LaForge KS, Tian M et al (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95:9608–9613
Mague SD, Blendy JA (2010) OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend 108:172–182
Oertel BG, Doehring A, Roskam B et al (2012) Genetic-epigenetic interaction modulates mu-opioid receptor regulation. Hum Mol Genet 21:4751–4760
Zhang Y, Wang D, Johnson AD et al (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618–33224
Kroslak T, Laforge KS, Gianotti RJ (2007) The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem 103:77–87
Oertel BG, Kettner M, Scholich K et al (2009) A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem 284:6530–6535
http://www.ensembl.org. Accessed 26 April 2014
Ide S, Han W, Kasai S et al (2005) Characterization of the 3′ untranslated region of the human mu-opioid receptor (MOR-1) mRNA. Gene 364:139–145
Wu Q, Law PY, Wei LN et al (2008) Post-transcriptional regulation of mouse mu opioid receptor (MOR1) via its 3′ untranslated region: a role for microRNA23b. FASEB J 22:4085–4095
Lötsch J, Geisslinger G (2005) Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med 11:82–89
Lötsch J, Geisslinger G (2010) A critical appraisal of human genotyping for pain therapy. Trends Pharmacol Sci 31:312–317
Yuferov V, Fussell D, LaForge KS et al (2004) Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics 14:793–804
Xuei X, Dick D, Flury-Wetherill L et al (2006) Association of the kappa-opioid system with alcohol dependence. Mol Psychiatry 11:1016–1024
Edenberg HJ, Wang J, Tian H et al (2008) A regulatory variation in OPRK1, the gene encoding the kappa-opioid receptor, is associated with alcohol dependence. Hum Mol Genet 17:1783–1789
Ashenhurst JR, Bujarski S, Ray LA (2012) Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol. Pharmacol Biochem Behav 103:253–259
Majewski J, Schwartzentruber J, Lalonde E et al (2011) What can exome sequencing do for you? J Med Genet 48:580–589
Sanger F, Coulson AR (1975) A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol 94:441–448
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 74:5463–5467
Maxam AM, Gilbert W (1977) A new method for sequencing DNA. Proc Natl Acad Sci U S A 74:560–564
Smith LM, Sanders JZ, Kaiser RJ et al (1986) Fluorescence detection in automated DNA sequence analysis. Nature 321:674–679
Hutchinson CA III (2007) DNA sequencing: bench to bedside and beyond. Nucleic Acids Res 35:6227–6237
Proudnikov D, Randesi M, Levran O et al (2012) Association of polymorphisms of the mu opioid receptor gene with the severity of HIV infection and response to HIV treatment. J Infect Dis 205:1745–1756
Hastie BA, Riley JL 3rd, Kaplan L et al (2012) Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain 153:1610–1619
Bortsov AV, Millikan RC, Belfer I (2012) μ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology 116:896–902
Wang SC, Tsou HH, Chung RH et al (2014) The association of genetic polymorphisms in the μ-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance. J Clin Psychopharmacol 34:205–211
Rhodin A, Grönbladh A, Ginya H et al (2013) Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects. Mol Brain 6:8
Metzker ML (2010) Sequencing technologies—the next generation. Nat Rev Genet 11:31–46
Cooper DN, Krawczak M, Antonorakis SE (1995) The nature and mechanisms of human gene mutation. In: Scriver C, Beaudet AL, Sly WS et al (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 259–291
Stenson PD, Ball EV, Howells K et al (2009) The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalized genomics. Hum Genomics 4:69–72
Singleton AB (2011) Exome sequencing: a transformative technology. Lancet Neurol 10:942–946
Su Z, Ning B, Fang H et al (2011) Next-generation sequencing and its applications in molecular diagnostics. Expert Rev Mol Diagn 11:333–343
Lötsch J, Geisslinger G (2006) Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 6:200–210
Deo AJ, Huang YY, Hodgkinson CA et al (2013) A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction. Psychiatr Genet 23:47–55
Lee MR, Gallen CL, Zhang X et al (2011) Functional polymorphism of the mu-opioid receptor gene (OPRM1) influences reinforcement learning in humans. PLoS One 6:e24203
Foo J-N, Liu J-J, Tan E-K (2012) Whole-genome and whole-exome sequencing in neurological diseases. Nat Rev Neurol 8:508–517
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Spampinato, S.M. (2015). Overview of Genetic Analysis of Human Opioid Receptors. In: Spampinato, S. (eds) Opioid Receptors. Methods in Molecular Biology, vol 1230. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1708-2_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1708-2_1
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-1707-5
Online ISBN: 978-1-4939-1708-2
eBook Packages: Springer Protocols