118A>G AND IVS2+691G>C POLYMORPHISMS OF OPRM1 GENE HAVE NO INFLUENCE ON COLD-PAIN SENSITIVITY AMONG HEALTHY OPIOID-NAIVE MALAY MALES
Abstract
Objective: Common polymorphisms of the mu-type opioid receptor (OPRM1) including 118A>G and IVS2+691G>C may affect experimental pain responses in healthy subjects, and the effect could be ethnic-dependent. The aim of this study was to investigate the influence of these OPRM1 polymorphisms on cold-pressor pain responses among healthy opioid-naive Malay males.
Methods: Pain-threshold, pain-tolerance, and pain-intensity in response to the cold pressor test (CPT) were measured in healthy opioid-naive Malay males. DNA was extracted from the collected venous blood before PCR-genotyping. Repeated measure analysis of variance (RM-ANOVA) was used to compare CPT responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) according to their genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes.
Results: A total of 152 participants were recruited. Both 118A>G and IVS2+691G>C polymorphisms were not associated with cold-pressor pain-threshold, pain-tolerance and pain-intensity despite using genotypes and allelic additive models and genotype dominant and recessive models (all p>0.05). Likewise, there were no significant associations between haplotypes and diplotypes for the 118A>G and IVS2+691G>C polymorphisms and the three cold-pain responses (all p>0.05).
Conclusion: The common OPRM1 polymorphisms (i.e., 118A>G and IVS2+691G>C), are not associated with cold-pressor pain responses in healthy opioid-naive Malay males. However, this may be unique for this particular ethnicity. Other polymorphisms may be more relevant for this population, and this should be further investigated.
Keywords: Cold pressor test (CPT), Mu-type opioid receptor (OPRM1), Opioid receptor, mu 1 gene (OPRM1), Pain-threshold, Pain-tolerance, Pain-intensity, Opioid-naive, Male, Malays
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References
Mizoguchi H, Narita M, Wu H, Suzuki T, Nagase H, Tseng LF. Differential involvement of mu-opioid receptors in endomorphin-and beta-endorphin-induced G-protein activation in the mouse pons/medulla. Neuroscience 2000; 100:835-9.
Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets 2012;13:230-46.
Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. Differential activation of G-proteins by mu-opioid receptor agonists. Br J Pharmacol 2006;147:671-80.
Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001;293:311-5.
Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances. J Med Genet 2012;49:1-9.
Govoni S, Regazzi M, Ranzani GN. Pain and the pharmacogenetics at the fuzzy border between pain physiopathology and pain treatment. Eur J Pain Suppl 2008;2 Suppl 1:5-12.
Lind AL, Gordh TE. Research on genes predisposing for chronic pain: a challenge for pain researchers in scandinavia. Scandinavian J Pain 2009;1 Suppl 1:24-6.
Lötsch J, Geisslinger G, Tegeder I. Genetic modulation of the pharmacological treatment of pain. Pharmacol Ther 2009;124:168-84.
Miaskowski C. Understanding the genetic determinants of pain and pain management. Semin Oncol Nurs 2009;25(2, Suppl 1):1-7.
Kim DH, Schwartz CE. The genetics of pain: implications for evaluation and treatment of spinal disease. Spine J 2010;10:827-40.
Kasai S, Ikeda K. Pharmacogenomics of the human μ-opioid receptor. Pharmacogenomics 2011;12:1305-20.
Shipton EA. Pharmacogenomics in acute pain. Trends Anaesthesia Critical Care 2011;1:117-22.
Hagelberg N, Aalto S, Tuominen L, Pesonen U, Nagren K, Hietala J, et al. Striatal mu-opioid receptor availability predicts cold pressor pain-threshold in healthy human subjects. Neurosci Lett 2012;521:11-4.
Fillingim RB, Kaplan L, Staud R, Ness TJ, Glover TL, Campbell CM, et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 2005;6:159-67.
Lotsch J, Stuck B, Hummel T. The human μ-opioid receptor gene polymorphism 118A>G decreases cortical activation in response to specific nociceptive stimulation. Behav Neurosci 2006;120:1218-24.
Hastie BA, Riley JL, Kaplan L, Herrera DG, Campbell CM, Virtusio K, et al. Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain 2012;153:1610-9.
Huang CJ, Liu HF, Su NY, Hsu YW, Yang CH, Chen CC, et al. Association between human opioid receptor genes polymorphisms and pressure pain sensitivity in females*. Anaesthesia 2008;63:1288-95.
Chen AC, Dworkin SF, Haug J, Gehrig J. Human pain responsivity in a tonic pain model: psychological determinants. Pain 1989;37:143-60.
Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend 2001;63:139-46.
Zahari Z, Lee CS, Tan SC, Mohamad N, Lee YY, Ismail R. Relationship between cold pressor pain-sensitivity and sleep quality in opioid-dependent males on methadone treatment. Peer J 2015;3:e839.
Wolf S, Hardy JD. Studies on pain. Observations on pain due to local cooling and on factors involved in the cold pressor†effect. J Clin Invest 1941;20:521-33.
Harris G, Rollman GB. The validity of experimental pain measures. Pain 1983;17:369-76.
Glynn CJ, Lloyd JW. The diurnal variation in perception of pain. Proc R Soc Med 1976;69:369-72.
Mohamed Nazar NI. Therapeutic drug monitoring in methadone maintenance therapy (mmt): an evaluation of genetic factors influencing clinical outcomes and serum concentrations of methadone: Ph. D Thesis, Universiti Sains Malaysia; 2013.
Cohen J. A power primer. Psychol Bull 1992;112:155-9.
Belfer I, Segall SK, Lariviere WR, Smith SB, Dai F, Slade GG, et al. Pain modality-and sex-specific effects of COMT genetic functional variants. Pain 2013;154:1368-76.
Tan EC, Tan CH, Karupathivan U, Yap EP. Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport 2003;14:569-72.
Zhang W, Chang YZ, Kan QC, Zhang LR, Lu H, Chu QJ, et al. Association of human μ-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia 2010;65:130-5.
Fukuda K, Hayashida M, Ide S, Saita N, Kokita Y, Kasai S, et al. Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery. Pain 2009;147:194-201.
Tan EC, Lim EC, Teo YY, Lim Y, Law HY, Sia AT. Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain. Mol Pain 2009;5:32.
Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, 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;95:9608-13.
Beyer A, Koch T, Schroder H, Schulz S, Hollt V. Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 2004;89:553-60.
Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005;280:32618-24.
Muralidharan A, Smith MT. Pain, analgesia and genetics. J Pharm Pharmacol 2011;63:1387-400.
Fillingim RB, Maixner W. Gender differences in the responses to noxious stimuli. Pain Forum 1995;4:209-21.
Alabas OA, Tashani OA, Tabasam G, Johnson MI. Gender role affects experimental pain responses: a systematic review with meta-analysis. Eur J Pain 2012;16:1211-23.
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447-85.
Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choiniere M. A systematic literature review of 10 y of research on sex/gender and experimental pain perception-part 1:are there really differences between women and men? Pain 2012;153:602-18.
Angst MS, Phillips NG, Drover DR, Tingle M, Ray A, Swan GE, et al. Pain sensitivity and opioid analgesia: a pharmacogenomic twin study. Pain 2012;153:1397-409.
Shavers VL, Bakos A, Sheppard VB. Race, ethnicity, and pain among the U. S. adult population. J Health Care Poor Underserved 2010;21:177-220.
Edwards CL, Fillingim RB, Keefe F. Race, ethnicity and pain. Pain 2001;94:133-7.
Carter LE, McNeil DW, Vowles KE, Sorrell JT, Turk CL, Ries BJ, et al. Effects of emotion on pain reports, tolerance and physiology. Pain Res Manag 2002;7:21-30.