Skip to main content

Advertisement

Log in

Is there genetic polymorphism evidence for individual human sensitivity to opiates?

  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Opiate analgesics have been widely used for severe acute pain and chronic cancer-related pain. Individual differences in the effectiveness of opiates and their side effects limit the clinical benefits and increase risks of drug abuse. Genetic factors might affect variations of opiate sensitivity. The mu opioid peptide receptor (MOP) is the principal site of pharmacologic actions for most clinically important opiate drugs. Recent studies using various knockout mice and recombinant-inbred strain CXBK mice have indicated that the analgesic effect of morphine is dependent on the amount of the MOP. There are more than 100 polymorphisms identified in the human MOP (OPRM1) gene. These polymorphisms might be correlated with OPRM1 mRNA stability and opiate sensitivity, including opiate analgesia, tolerance, and dependence. More precise studies on the relationship between gene polymorphisms and opiate sensitivity will enable realization of personalized pain treatment by predicting opiate sensitivity and requirement for each patient.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Cleeland CS, Gonin R, Hatfield AK, et al.: Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994, 330:592–596.

    Article  PubMed  CAS  Google Scholar 

  2. Ready LB: Acute perioperative pain. In Anesthesia, edn 5. Edited by Miller RD. Philadelphia: Churchill Livingstone Inc.; 2000:2323–2350.

    Google Scholar 

  3. Foley KM: The treatment of cancer pain. N Engl J Med 1985, 313:84–95.

    Article  PubMed  CAS  Google Scholar 

  4. World Health Organization: Cancer Pain Relief. Geneva, Switzerland: World Health Organization; 1986.

    Google Scholar 

  5. World Health Organization Expert Committee: Cancer Pain Relief and Palliative Care. Geneva, Switzerland: World Health Organization; 1990.

    Google Scholar 

  6. World Health Organization: Cancer Pain Relief with a Guide to Opioid Availability, edn 2. Geneva, Switzerland: World Health Organization; 1996.

    Google Scholar 

  7. Ikeda K, Ide S, Han W, et al.: How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 2005, 26:311–317.

    Article  PubMed  CAS  Google Scholar 

  8. Han W, Ide S, Sora I, et al.: A possible genetic mechanism underlying individual and interstrain differences in opioid actions: focus on the mu opioid receptor gene. Ann N Y Acad Sci 2004, 1025:370–375.

    Article  PubMed  CAS  Google Scholar 

  9. Mogil JS: The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci U S A 1999, 96:7744–7751.

    Article  PubMed  CAS  Google Scholar 

  10. Uhl GR, Sora I, Wang Z: The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci U S A 1999, 96:7752–7755.

    Article  PubMed  CAS  Google Scholar 

  11. Rowlingson JC, Murphy TM: Chronic pain. In Anesthesia, edn 5. Edited by Miller RD. Philadelphia: Churchill Livingstone Inc.; 2000:2351–2379.

    Google Scholar 

  12. Inturrisi CE: Clinical pharmacology of opioids for pain. Clin J Pain 2002, 18:S3–S13.

    Article  PubMed  Google Scholar 

  13. Goldstein FJ: Adjuncts to opioid therapy. J Am Osteopath Assoc 2002, 102:S15–S21.

    PubMed  Google Scholar 

  14. Mogil JS, Yu L, Basbaum AI: Pain genes?: natural variation and transgenic mutants. Annu Rev Neurosci 2000, 23:777–811.

    Article  PubMed  CAS  Google Scholar 

  15. Kim H, Neubert JK, San Miguel A, et al.: Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 2004, 109:488–496.

    Article  PubMed  Google Scholar 

  16. Sora I, Elmer G, Funada M, et al.: Mu opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo mu receptor reserve. Neuropsychophar-macology 2001, 25:41–54.

    CAS  Google Scholar 

  17. Kieffer BL, Gaveriaux-Ruff C: Exploring the opioid system by gene knockout. Prog Neurobiol 2002, 66:285–306.

    Article  PubMed  CAS  Google Scholar 

  18. Ide S, Han W, Kasai S, et al.: Characterization of the 3′ untranslated region of the human mu-opioid receptor (MOR-1) mRNA. Gene 2005, 364:139–145.

    Article  PubMed  CAS  Google Scholar 

  19. Sora I, Takahashi N, Funada M, et al.: Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci U S A 1997, 94:1544–1549.

    Article  PubMed  CAS  Google Scholar 

  20. Kieffer BL: Opioid: first lessons from knockout mice. Trends Pharmacol Sci 1999, 20:19–26.

    Article  PubMed  CAS  Google Scholar 

  21. Matthes HW, Smadja C, Valverde O, et al.: Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor. J Neurosci 1998, 18:7285–7295.

    PubMed  CAS  Google Scholar 

  22. Ikeda K, Ichikawa T, Kobayashi T, et al.: Unique behavioural phenotypes of recombinant-inbred CXBK mice: partial deficiency of sensitivity to mu-and kappa-agonists. Neurosci Res 1999, 34:149–155.

    Article  PubMed  CAS  Google Scholar 

  23. Ikeda K, Kobayashi T, Ichikawa T, et al.: The untranslated region of (mu)-opioid receptor mRNA contributes to reduced opioid sensitivity in CXBK mice. J Neurosci 2001, 21:1334–1339.

    PubMed  CAS  Google Scholar 

  24. Han W, Kasai S, Hata H, et al.: Intracisternal A-particle element in the 3′ noncoding region of the mu-opioid receptor gene in CXBK mice: a new genetic mechanism underlying differences in opioid sensitivity. Pharmacogenet Genomics 2006, 16:451–460.

    Article  PubMed  CAS  Google Scholar 

  25. Kasai S, Han W, Ide S, et al.: Involvement of the 3′ noncoding region of the mu opioid receptor gene in morphine-induced analgesia. Psychiatry Clin Neurosci 2006, 60:11–17.

    Article  Google Scholar 

  26. Bond C, LaForge KS, Tian M, et al.: 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 1998, 95:9608–9613.

    Article  PubMed  CAS  Google Scholar 

  27. Hoehe MR, Kopke K, Wendel B, et al.: Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet 2000, 9:2895–2908.

    Article  PubMed  CAS  Google Scholar 

  28. Ide S, Kobayashi H, Tanaka K, et al.: Gene polymorphisms of the mu opioid receptor in methamphetamine abusers. Ann N Y Acad Sci 2004, 1025:316–324.

    Article  PubMed  CAS  Google Scholar 

  29. Conne B, Stutz A, Vassalli JD: The 3′ untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med 2000, 6:637–641.

    Article  PubMed  CAS  Google Scholar 

  30. Smolka M, Sander T, Schmidt LG, et al.: Mu-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal. Psychoneuroendocrinology 1999, 24:629–638.

    Article  PubMed  CAS  Google Scholar 

  31. Shi J, Hui L, Xu Y, et al.: Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 2002, 19:459–460.

    Article  PubMed  CAS  Google Scholar 

  32. Lotsch J, Skarke C, Grosch S, et al.: The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002, 12:3–9.

    Article  PubMed  CAS  Google Scholar 

  33. Ide S, Kobayashi H, Ujike H, et al.: Linkage disequilibrium and association with methamphetamine dependence/psychosis of mu-opioid receptor gene polymorphisms. Pharmacogenomics J 2006, 6:179–188.

    Article  PubMed  CAS  Google Scholar 

  34. Ikeda K, Kobayashi T, Kumanishi T, et al.: Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Neurosci Res 2002, 44:121–131.

    Article  PubMed  CAS  Google Scholar 

  35. Kobayashi T, Ikeda K: G protein-activated inwardly rectifying potassium channels as potential therapeutic targets. Curr Pharm Des 2006, 12:4513–4523.

    Article  PubMed  CAS  Google Scholar 

  36. Rogers JF, Nafziger AN, Bertino JS Jr: Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs. Am J Med 2002, 113:746–750.

    Article  PubMed  CAS  Google Scholar 

  37. Ueda H: Locus-specific involvement of anti-opioid systems in morphine tolerance and dependence. Ann N Y Acad Sci 2004, 1025:376–382.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kazutaka Ikeda PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagashima, M., Katoh, R., Sato, Y. et al. Is there genetic polymorphism evidence for individual human sensitivity to opiates?. Curr Pain Headache Rep 11, 115–123 (2007). https://doi.org/10.1007/s11916-007-0008-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-007-0008-8

Keywords

Navigation