Effect of PDYN rs2281285, rs2235749 and rs910080 gene polymorphisms on the intensity of depression symptoms and negative craving in heroin addicts
Keywords:heroin dependence, dynorphins, PDYN variation, depression, negative craving
- The effects of prodynorphin (PDYN) gene haplotypes containing polymorphisms rs910080, rs2281285, rs2225749 (SNPs) on heroin dependence risk were examined for the first time.
- Gene polymorphisms were genotyped (PCR-RFLP) in 100 heroin addicts and 108 healthy controls. Craving and depressive symptoms were measured by the Substance Craving Scale and Beck Depression Inventory-II, respectively.
- Individuals with the AAA haplotype are more prone to heroin dependence; rs2281285 and rs2225749 affect the intensity of depressive symptoms; rs2225749 contributes to induction of negative craving.
- These findings show the association of PDYN haplotypes composed of rs2281285, rs2235749 and rs910080 with heroin dependence.
Abstract: The present study was undertaken to explore whether prodynorphin (PDYN) polymorphisms have an effect on the intensity of depressive symptoms and negative craving in heroin addicts in a sample of 100 heroin addicts and 108 controls. PDYN rs2281285, rs2225749 and rs910080 polymorphisms were analyzed by PCR-RFLP. Craving and the intensity of depressive symptoms were measured by the Substance Craving Scale and the Beck Depression Inventory-II, respectively. A significant association between depression severity and PDYN rs2281285 (P=0.026) and rs2225749 (P=0.038) polymorphisms was detected. PDYN rs2225749 variation showed a trend association with increased negative craving (P=0.066). We also examined the associations between heroin dependence and PDYN rs2281285, rs2225749 and rs910080 gene polymorphisms at the gene and haplotype levels. The AAA haplotype was more frequent in heroin addicts and shown to be significantly associated with increased risk for heroin dependence (OR, 8.922; 95% CI, 1.116-71.313; P<0.05). PDYN rs2281285 and rs2225749 variations affected the intensity of depressive symptoms, and PDYN rs2225749 polymorphism may contribute to the induction of negative craving in heroin addicts. Haplotype analysis revealed for the first time that addicts with the AAA haplotype of PDYN gene may be more prone to heroin dependence.
Mysels D, Sullivan MA. The Kappa-Opiate Receptor Impacts the Pathophysiology and Behavior of Substance Use. Am J Addict. 2009;18:272-76.
Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry. 2014;5:170.
Karkhanis A, Holleran KM, Jones SR. Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction. Int Rev Neurobiol. 2017;136:53-88.
Knoll AT, Carlezon Jr WA. Dynorphin, stress, and depression. Brain Res. 2010;1314:56-73.
Al-Hakeim HK, Al-Fadhel SZ, Al-Dujaili AH, Maes M. In major depression, increased kappa and mu opioid receptor levels are associated with immune activation. Acta Neuropsychiatr. 2020;32:99-108.
Shippenberg T. The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders? Neuropsychopharmacology. 2009;34:247.
Yuanyuan J, Rui S, Hua T, Jingjing C, Cuola D, Yuhui S, Shuguang W. Genetic association analyses and meta-analysis of Dynorphin-Kappa Opioid system potential functional variants with heroin dependence. Neurosci Lett. 2018;685:75-82.
Butelman ER, Yuferov V, Kreek MJ. κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci. 2012;35:587-96.
Wang YH, Sun JF, Tao YM, Chi ZQ, Liu JG. The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol Sin. 2010;31:1065-70.
Shahkarami K, Vousooghi N, Golab F, Mohsenzadeh A, Baharvand P, Sadat-Shirazi M-S, Babhadi-Ashar N, Shakeri A, Zarrindast MR. Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder. Drug Alcohol Depend. 2019;205:107638.
Anderson SAR, Michaelides M, Zarnegar P, Ren Y, Fagergren P, Thanos PK, Wang G-J, Bannon M, Neumaier JF, Keller E, Volkow ND, Hurd YL. Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J Clin Invest. 2013;123:5334-41.
Kakko J, Alho H, Baldacchino A, Molina R, Nava FA, Shaya G. Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice. Front Psychiatry. 2019;10:592.
Lutz PE, Ayranci G, Chu-Sin-Chung P, Matifas A, Koebel P, Filliol D, Befort K, Ouagazzal AM, Kieffer BL. Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology. 2014;39:2694-2705.
Welsch L, Bailly J, Darcq E, Kieffer BL. The Negative Affect of Protracted Opioid Abstinence: Progress and Perspectives From Rodent Models. Biol Psychiatry. 2020;87:54-63.
Kreek MJ, Reed B, Butelman ER. Current status of opioid addiction treatment and related preclinical research. Sci Adv. 2019;5:eaax9140.
Xu K, Seo D, Hodgkinson C, Hu Y, Goldman D, Sinha R. A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk. Transl Psychiatry. 2013;3:e292.
Clarke T-K, Krause K, Li T, Schumann G. An association of prodynorphin polymorphisms and opioid dependence in females in a Chinese population. Addict Biol. 2009;14:366-70.
Wei SG, Zhu YS, Lai JH, Xue HX, Chai ZQ, Li SB. Association between heroin dependence and prodynorphin gene polymorphisms. Brain Res Bull. 2011;85:238-42.
Clarke TK, Ambrose-Lanci L, Ferraro TN, Berrettini WH, Kampman KM, Dackis CA, Pettinati HM, O'Brien CP, Oslin DW, Lohoff FW. Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction. Genes Brain Behav. 2012;11: 415-23.
Hashemi M, Shakiba M, Sanaei S, Shahkar G, Rezaei M, Mojahed A, Bahari G. Evaluation of prodynorphin gene polymorphisms and their association with heroin addiction in a sample of the southeast Iranian population. Mol Biol Res Commun 2018;7:1-6.
Wang CW, Ma M, Lu WG, Luo RQ. Association between prodynorphin gene polymorphisms and opioid dependence susceptibility: a metaanalysis. BMC Psychiatry. 2019;19:281.
Yuferov V, Ji F, Nielsen DA, Levran O, Ho A, Morgello S, Shi R, Ott J, Kreek MJ. A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain. Neuropsychopharmacology. 2009;34:1185-97.
Evren C, Gürol DT, Ögel K. Reliability and validity of the Penn Alcohol Craving Scale (PACS) Revised Version for substance craving in male substance dependent inpatients. Turk J Psych. 2011;22:70-85. Turkish.
Hisli N. Reliability and validity of Beck Depression Inventory among university students. Turk Psikoloji Dergisi. 1989;7:3-13. Turkish.
Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97-8.
Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z, He L, Shi Y. A partition-ligation-combination-suBDI-IIvision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res. 2009;19:519-23.
Karpyak VM, Winham SJ, Preuss UW, Zill P, Cunningham JM, Walker DL, Lewis KA, Geske JR, Colby CL, Abulseoud OA, Hall-Flavin DK, Loukianova LL, Schneekloth, TD, Frye MA, Bazov I, Heit JA, Bakalkin G, Mrazek DA, Biernacka JM. Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states. Int J Neuropsychopharmacol. 2013;16:975-85.
Preuss UW, Winham SJ, Biernacka JM, Geske JR, Bakalkin G, Koller G, Zill P, Soyka M, Karpyak VM. PDYN rs2281285 Variant Association with Drinking to Avoid Emotional or Somatic Discomfort. PLoS One. 2013;8:e78688.
Winham SJ, Preuss UW, Geske JR, Zill P, Heit JA, Bakalkin G, Biernacka JM, Karpyak VM. Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent. Sci Rep. 2015;5:15670.
Saify K, Saadat I, Saadat M. Association between VNTR polymorphism in promoter region of prodynorphin (PDYN) gene and heroin dependence. Psychiatry Res. 2014; 219:690-92.
Nikoshkov A, Drakenberg K, Wang X, Horvath MCs, Keller E, Hurd YL. Opioid neuropeptide genotypes in relation to heroin abuse: dopamine tone contributes to reversed mesolimbic proenkephalin expression. Proc Natl Acad Sci USA. 2008;105:786-91.
Egervari G, Jutras-Aswad D, Landry J, Miller ML, Anderson SA, Michaelides M., Jacobs, MM, Pete, C, Yiannoulos G, Liu X, Hurd YL. A Functional 3'UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits. Neuropsychopharmacology. 2016;41:2512-220.
Josefsson K, Merjonen P, Jokela M, Pulkki-Råback L, Keltikangas-Järvinen L. Personality Profiles Identify Depressive Symptoms over Ten Years? A Population-Based Study. Depress Res Treat. 2011;2011:431314.
Randesi M, Rotrosen J, Nunes EV, Lee JD, Novo P, Levran O, Ott J, Pavlicova M, Scodes J, Kreek MJ. Variants of opioid genes and response to treatment of opioid use disorder with buprenorphine-naloxone versus extended-release naltrexone in Caucasians. Am J Drug Alcohol Abuse. 2020;46:761-68.
Chavkin C, Koob GF. Dynorphin, Dysphoria, and Dependence: the Stress of Addiction. Neuropsychopharmacology. 2016;41:373-74.
Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF. Role of endogenous opioid system in the regulation of the stress response. Prog Neuro-Psychopharmacol Biol Psychiatry. 2001;25:729-41.
Kelley AE, Bakshi VP, Haber SN, Steininger TL, Will MJ, Zhang M. Opioid modulation of taste hedonics within the ventral striatum. Physiol Behav. 2002;76:365-77.
Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36:195-206.
How to Cite
Copyright (c) 2021 Archives of Biological Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.