Skip to main content

Overview of Genetic Analysis of Human Opioid Receptors

  • Protocol
  • First Online:
Opioid Receptors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1230))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pasternak GW, Pan YX (2013) Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 65:1257–1317

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Cox BM (2013) Recent developments in the study of opioid receptors. Mol Pharmacol 83:723–728

    Article  PubMed  CAS  Google Scholar 

  3. Butelman ER, Yuferov V, Kreek MJ (2012) Kappa opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci 35:587–596

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363–1381

    PubMed  CAS  PubMed Central  Google Scholar 

  5. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Crist RC, Berrettini WH (2013) Pharmacogenetics of OPRM1. Pharmacol Biochem Behav. doi:10.1016/j.pbb.2013.10.018

    PubMed  Google Scholar 

  7. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. 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

    Article  PubMed  Google Scholar 

  9. Holliday KL, Nicholl BI, Macfarlane GJ et al (2009) Do genetic predictors of pain sensitivity associate with persistent widespread pain? Mol Pain 5:56

    Article  PubMed  PubMed Central  Google Scholar 

  10. Anderson KO, Green CR, Payne R (2009) Racial and ethnic disparities in pain: causes and consequences of unequal care. J Pain 10:1187–1204

    Article  PubMed  Google Scholar 

  11. 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

    Article  PubMed  Google Scholar 

  12. 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

    PubMed  PubMed Central  Google Scholar 

  13. 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

    Article  PubMed  Google Scholar 

  14. 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

    Article  PubMed  Google Scholar 

  15. 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

    Article  PubMed  Google Scholar 

  16. Campbell CM, Edwards RR, Fillingim RB (2005) Ethnic differences in responses to multiple experimental pain stimuli. Pain 113:20–26

    Article  PubMed  Google Scholar 

  17. 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

    Article  PubMed  Google Scholar 

  18. 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

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Mague SD, Blendy JA (2010) OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend 108:172–182

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Oertel BG, Doehring A, Roskam B et al (2012) Genetic-epigenetic interaction modulates mu-opioid receptor regulation. Hum Mol Genet 21:4751–4760

    Article  PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. 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

    PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. http://www.ensembl.org. Accessed 26 April 2014

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Lötsch J, Geisslinger G (2005) Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med 11:82–89

    Article  PubMed  Google Scholar 

  30. Lötsch J, Geisslinger G (2010) A critical appraisal of human genotyping for pain therapy. Trends Pharmacol Sci 31:312–317

    Article  PubMed  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. Xuei X, Dick D, Flury-Wetherill L et al (2006) Association of the kappa-opioid system with alcohol dependence. Mol Psychiatry 11:1016–1024

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Majewski J, Schwartzentruber J, Lalonde E et al (2011) What can exome sequencing do for you? J Med Genet 48:580–589

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 74:5463–5467

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Maxam AM, Gilbert W (1977) A new method for sequencing DNA. Proc Natl Acad Sci U S A 74:560–564

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Smith LM, Sanders JZ, Kaiser RJ et al (1986) Fluorescence detection in automated DNA sequence analysis. Nature 321:674–679

    Article  PubMed  CAS  Google Scholar 

  40. Hutchinson CA III (2007) DNA sequencing: bench to bedside and beyond. Nucleic Acids Res 35:6227–6237

    Article  Google Scholar 

  41. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Hastie BA, Riley JL 3rd, Kaplan L et al (2012) Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain 153:1610–1619

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Bortsov AV, Millikan RC, Belfer I (2012) μ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology 116:896–902

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. 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

    Article  PubMed  CAS  Google Scholar 

  45. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Metzker ML (2010) Sequencing technologies—the next generation. Nat Rev Genet 11:31–46

    Article  PubMed  CAS  Google Scholar 

  47. 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

    Google Scholar 

  48. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Singleton AB (2011) Exome sequencing: a transformative technology. Lancet Neurol 10:942–946

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. 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

    PubMed  Google Scholar 

  51. Lötsch J, Geisslinger G (2006) Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 6:200–210

    Article  PubMed  Google Scholar 

  52. 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

    Article  PubMed  CAS  Google Scholar 

  53. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. 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

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Santi M. Spampinato .

Editor information

Editors and Affiliations

Rights and permissions

Reprints 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

Publish with us

Policies and ethics