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Association of the mu-opioid receptor gene with smoking cessation

Abstract

We investigated the association of the OPRM1 genotype with long-term smoking cessation and change in body mass index (BMI) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy (NRT) patch or placebo in a randomized controlled trial, and were followed-up over an 8-year period following their initial cessation attempt. We also investigated possible sex differences in these relationships, given evidence for sex differences in smoking cessation and central opioid mechanisms, as well as some evidence for sex differences in response to NRT. Our results indicate that OPRM1 genotype may moderate the effect of transdermal nicotine patch compared to placebo during active treatment, with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch. Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt, with ex-smokers demonstrating an increase in BMI, and this increase being greater in female subjects than in male subjects. We did not observe any association of OPRM1 genotype with change in BMI, although there was a trend for genotype to influence the observed sex difference in change in BMI over time. Future studies should attempt to replicate these findings, and investigate the relationship between both short- and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes. Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption.

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References

  1. Doll R, Peto R, Boreham J, Sutherland I . Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004; 328: 1519.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hughes JR . Motivating and helping smokers to stop smoking. J Gen Intern Med 2003; 18: 1053–1057.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Munafo MR, Shields AE, Berrettini WH, Patterson F, Lerman C . Pharmacogenetics and nicotine addiction treatment. Pharmacogenomics 2005; 6: 211–223.

    Article  CAS  PubMed  Google Scholar 

  4. Munafo MR, Lerman C, Niaura R, Shields AE, Swan GE . Smoking cessation treatment: pharmacogenetic assessment. Curr Opin Mol Ther 2005; 7: 202–208.

    CAS  PubMed  Google Scholar 

  5. Munafo M, Clark T, Johnstone E, Murphy M, Walton R . The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res 2004; 6: 583–597.

    Article  CAS  PubMed  Google Scholar 

  6. Boyadjieva NI, Sarkar DK . The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci 1997; 61: PL59–PL66.

    Article  CAS  PubMed  Google Scholar 

  7. Robinson TE, Berridge KC . The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 1993; 18: 247–291.

    Article  CAS  PubMed  Google Scholar 

  8. Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis M, Patterson F et al. Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006; 31: 231–242.

    Article  CAS  PubMed  Google Scholar 

  9. Yudkin P, Munafo M, Hey K, Roberts S, Welch S, Johnstone E et al. Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ 2004; 328: 989–990.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Munafo MR, Johnstone EC, Wileyto EP, Shields PG, Elliot KM, Lerman C . Lack of association of 5-HTTLPR genotype with smoking cessation in a nicotine replacement therapy randomized trial. Cancer Epidemiol Biomarkers Prev 2006; 15: 398–400.

    Article  CAS  PubMed  Google Scholar 

  11. Lerman C, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, Restine S et al. The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics J 2004; 4: 184–192.

    Article  CAS  PubMed  Google Scholar 

  12. Gianoulakis C . Influence of the endogenous opioid system on high alcohol consumption and genetic predisposition to alcoholism. J Psychiatry Neurosci 2001; 26: 304–318.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Pastor R, Aragon CM . The role of opioid receptor subtypes in the development of behavioral sensitization to ethanol. Neuropsychopharmacology 2005; 31: 1489–1499.

    Article  PubMed  Google Scholar 

  14. Davenport KE, Houdi AA, Van Loon GR . Nicotine protects against mu-opioid receptor antagonism by beta-funaltrexamine: evidence for nicotine-induced release of endogenous opioids in brain. Neurosci Lett 1990; 113: 40–46.

    Article  CAS  PubMed  Google Scholar 

  15. Johnson SW, North RA . Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 1992; 12: 483–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dilts RP, Kalivas PW . Autoradiographic localization of mu-opioid and neurotensin receptors within the mesolimbic dopamine system. Brain Res 1989; 488: 311–327.

    Article  CAS  PubMed  Google Scholar 

  17. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ . Anatomy of CNS opioid receptors. Trends Neurosci 1988; 11: 308–314.

    Article  CAS  PubMed  Google Scholar 

  18. Xi ZX, Stein EA . GABAergic mechanisms of opiate reinforcement. Alcohol Alcohol 2002; 37: 485–494.

    Article  CAS  PubMed  Google Scholar 

  19. Lee FJ, Wang YT, Liu F . Direct receptor cross-talk can mediate the modulation of excitatory and inhibitory neurotransmission by dopamine. J Mol Neurosci 2005; 26: 245–252.

    Article  CAS  PubMed  Google Scholar 

  20. Kelley AE, Stinus L, Iversen SD . Interactions between D-ala-met-enkephalin, A10 dopaminergic neurones, and spontaneous behaviour in the rat. Behav Brain Res 1980; 1: 3–24.

    Article  CAS  PubMed  Google Scholar 

  21. 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: 32618–32624.

    Article  CAS  PubMed  Google Scholar 

  22. 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 USA 1998; 95: 9608–9613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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: 553–560.

    Article  CAS  PubMed  Google Scholar 

  24. Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL . A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 2001; 276: 3130–3137.

    Article  CAS  PubMed  Google Scholar 

  25. Ray LA, Hutchison KE . A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res 2004; 28: 1789–1795.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang L, Kendler KS, Chen X . The mu-opioid receptor gene and smoking initiation and nicotine dependence. Behav Brain Funct 2006; 2: 28.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sullivan PF, Neale BM, van den Oord E, Miles MF, Neale MC, Bulik CM et al. Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 23–36.

    Article  Google Scholar 

  28. Becker A, Grecksch G, Kraus J, Loh HH, Schroeder H, Hollt V . Rewarding effects of ethanol and cocaine in mu opioid receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 2002; 365: 296–302.

    Article  CAS  PubMed  Google Scholar 

  29. Berrendero F, Kieffer BL, Maldonado R . Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice. J Neurosci 2002; 22: 10935–10940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Contarino A, Picetti R, Matthes HW, Koob GF, Kieffer BL, Gold LH . Lack of reward and locomotor stimulation induced by heroin in mu-opioid receptor-deficient mice. Eur J Pharmacol 2002; 446: 103–109.

    Article  CAS  PubMed  Google Scholar 

  31. Hall FS, Sora I, Uhl GR . Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology (Berl) 2001; 154: 43–49.

    Article  CAS  Google Scholar 

  32. Hall FS, Goeb M, Li XF, Sora I, Uhl GR . Micro-opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine-induced locomotion. Brain Res Mol Brain Res 2004; 121: 123–130.

    Article  CAS  PubMed  Google Scholar 

  33. Bohadana A, Nilsson F, Rasmussen T, Martinet Y . Gender differences in quit rates following smoking cessation with combination nicotine therapy: influence of baseline smoking behavior. Nicotine Tob Res 2003; 5: 111–116.

    Article  PubMed  Google Scholar 

  34. Munafo M, Bradburn M, Bowes L, David S . Are there sex differences in transdermal nicotine replacement therapy patch efficacy? A meta-analysis. Nicotine Tob Res 2004; 6: 769–776.

    Article  CAS  PubMed  Google Scholar 

  35. Perkins KA, Donny E, Caggiula AR . Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1999; 1: 301–315.

    Article  CAS  PubMed  Google Scholar 

  36. Cicero TJ, Aylward SC, Meyer ER . Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 2003; 74: 541–549.

    Article  CAS  PubMed  Google Scholar 

  37. Craft RM, Kalivas PW, Stratmann JA . Sex differences in discriminative stimulus effects of morphine in the rat. Behav Pharmacol 1996; 7: 764–778.

    CAS  PubMed  Google Scholar 

  38. Lynch WJ, Carroll ME . Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 1999; 144: 77–82.

    Article  CAS  Google Scholar 

  39. Zubieta JK, Dannals RF, Frost JJ . Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry 1999; 156: 842–848.

    Article  CAS  PubMed  Google Scholar 

  40. Micevych PE, Rissman EF, Gustafsson JA, Sinchak K . Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization. J Neurosci Res 2003; 71: 802–810.

    Article  CAS  PubMed  Google Scholar 

  41. Mills RH, Sohn RK, Micevych PE . Estrogen-induced mu-opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y-Y1 receptor activation in the arcuate nucleus of female rats. J Neurosci 2004; 24: 947–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ray R, Jepson C, Patterson F, Strasser A, Rukstalis M, Perkins K et al. Association of OPRM1 A118G variant with the relative reinforcing value of nicotine. Psychopharmacology (Berl) 2006; 188: 355–363.

    Article  CAS  Google Scholar 

  43. Clark MM, Hurt RD, Croghan IT, Patten CA, Novotny P, Sloan JA et al. The prevalence of weight concerns in a smoking abstinence clinical trial. Addict Behav 2006; 31: 1144–1152.

    Article  PubMed  Google Scholar 

  44. Samet JM . The 1990 report of the surgeon general: the health benefits of smoking cessation. Am Rev Respir Dis 1990; 142: 993–994.

    Article  CAS  PubMed  Google Scholar 

  45. Hall SM, Havassy BE . Commitment to abstinence and relapse to tobacco, alcohol, and opiates. NIDA Res Monogr 1986; 72: 118–135.

    CAS  PubMed  Google Scholar 

  46. Grunberg NE . Nicotine as a psychoactive drug: appetite regulation. Psychopharmacol Bull 1986; 22: 875–881.

    CAS  PubMed  Google Scholar 

  47. Grunberg NE, Bowen DJ, Winders SE . Effects of nicotine on body weight and food consumption in female rats. Psychopharmacology (Berl) 1986; 90: 101–105.

    Article  CAS  Google Scholar 

  48. Miyata G, Meguid MM, Fetissov SO, Torelli GF, Kim HJ . Nicotine's effect on hypothalamic neurotransmitters and appetite regulation. Surgery 1999; 126: 255–263.

    Article  CAS  PubMed  Google Scholar 

  49. Hatsukami DK, Hughes JR, Pickens RW, Svikis D . Tobacco withdrawal symptoms: an experimental analysis. Psychopharmacology (Berl) 1984; 84: 231–236.

    Article  CAS  Google Scholar 

  50. Perkins KA, Epstein LH, Sexton JE, Pastor S . Effects of smoking cessation on consumption of alcohol and sweet, high-fat foods. J Subst Abuse 1990; 2: 287–297.

    Article  CAS  PubMed  Google Scholar 

  51. Spring B, Wurtman J, Gleason R, Wurtman R, Kessler K . Weight gain and withdrawal symptoms after smoking cessation: a preventive intervention using d-fenfluramine. Health Psychol 1991; 10: 216–223.

    Article  CAS  PubMed  Google Scholar 

  52. Swan GE, Carmelli D . Characteristics associated with excessive weight gain after smoking cessation in men. Am J Public Health 1995; 85: 73–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Munafo MR, Murphy MF, Johnstone EC . Smoking cessation, weight gain, and DRD4 -521 genotype. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 398–402.

    Article  Google Scholar 

  54. John U, Meyer C, Rumpf HJ, Hapke U, Schumann A . Predictors of increased body mass index following cessation of smoking. Am J Addict 2006; 15: 192–197.

    Article  PubMed  Google Scholar 

  55. Williamson DF, Madans J, Anda RF, Kleinman JC, Giovino GA, Byers T . Smoking cessation and severity of weight gain in a national cohort. N Engl J Med 1991; 324: 739–745.

    Article  CAS  PubMed  Google Scholar 

  56. Fox CS, Heard-Costa NL, Wilson PW, Levy D, D'Agostino Sr RB, Atwood LD . Genome-wide linkage to chromosome 6 for waist circumference in the Framingham Heart Study. Diabetes 2004; 53: 1399–1402.

    Article  CAS  PubMed  Google Scholar 

  57. Appleyard SM, Hayward M, Young JI, Butler AA, Cone RD, Rubinstein M et al. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 2003; 144: 1753–1760.

    Article  CAS  PubMed  Google Scholar 

  58. Low MJ, Hayward MD, Appleyard SM, Rubinstein M . State-dependent modulation of feeding behavior by proopiomelanocortin-derived beta-endorphin. Ann NY Acad Sci 2003; 994: 192–201.

    Article  CAS  PubMed  Google Scholar 

  59. Filozof C, Fernandez Pinilla MC, Fernandez-Cruz A . Smoking cessation and weight gain. Obes Rev 2004; 5: 95–103.

    Article  CAS  PubMed  Google Scholar 

  60. Wewers ME, Dhatt RK, Snively TA, Tejwani GA . The effect of chronic administration of nicotine on antinociception, opioid receptor binding and met-enkelphalin levels in rats. Brain Res 1999; 822: 107–113.

    Article  CAS  PubMed  Google Scholar 

  61. Mayer P, Hollt V . Pharmacogenetics of opioid receptors and addiction. Pharmacogenet Genomics 2006; 16: 1–7.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet 2006; 15: 807–819.

    Article  CAS  PubMed  Google Scholar 

  63. ICRF. Effectiveness of a nicotine patch in helping people stop smoking: results of a randomised trial in general practice. BMJ 1993; 306: 1304–1308.

  64. Johnstone EC, Yudkin PL, Hey K, Roberts SJ, Welch SJ, Murphy MF et al. Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics 2004; 14: 83–90.

    Article  CAS  PubMed  Google Scholar 

  65. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was funded by a Cancer Research UK Programme Grant.

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Correspondence to M R Munafò.

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Dr Walton is Chief Scientific officer of G-Nostics Ltd.

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Munafò, M., Elliot, K., Murphy, M. et al. Association of the mu-opioid receptor gene with smoking cessation. Pharmacogenomics J 7, 353–361 (2007). https://doi.org/10.1038/sj.tpj.6500432

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