Heroin and methamphetamine (METH) addiction continues to be a major social, economic and therapeutic problem worldwide. The opioid pathway may mediate the effects of addictive drugs. However, the potential correlation between the κ1 opioid receptor (OPRK1) and drug addiction has not yet been characterized. The aim of the present study was to investigate the potential association between methylation of the OPRK1 promoter and substance abuse. Bisulfite pyrosequencing technology was used to determine the levels of OPRK1 promoter methylation in 60 drug abusers (30 heroin and 30 METH addicts) and 52 controls, observed to exhibit no significant differences in age or gender. The results indicated that levels of OPRK1 promoter methylation were significantly higher in drug addicts when compared with controls (P=2.43×10-4). Significant correlations between OPRK1 promoter methylation and the length and frequency of drug use were also observed in male heroin addicts (length: r=0.661, P=0.007; frequency: r=-0.684, P=0.005). In addition, a luciferase reporter gene assay indicated that the OPRK1 promoter fragment was able to regulate gene expression (fold change between two groups >32.12, P≤0.0001). In conclusion, results of the present study indicate that methylation of the OPRK1 promoter contributes to the pathophysiology of drug addiction.

译文

海洛因和甲基苯丙胺(METH)成瘾仍然是全球范围内的主要社会,经济和治疗问题。阿片类药物途径可能介导成瘾药物的作用。然而,κ1阿片受体(OPRK1)和药物成瘾之间的潜在相关性尚未被表征。本研究的目的是研究OPRK1启动子的甲基化与药物滥用之间的潜在联系。使用亚硫酸氢盐焦磷酸测序技术确定60名吸毒者(30名海洛因和30名METH吸毒者)和52名对照的OPRK1启动子甲基化水平,观察到它们在年龄或性别上均无显着差异。结果表明,吸毒成瘾者的OPRK1启动子甲基化水平明显高于对照组(P = 2.43×10-4)。在男性海洛因成瘾者中,还观察到OPRK1启动子甲基化与吸毒时间和频率之间存在显着相关性(长度:r = 0.661,P = 0.007;频率:r = -0.684,P = 0.005)。另外,荧光素酶报告基因测定表明OPRK1启动子片段能够调节基因表达(两组之间的倍数变化> 32.12,P≤0.0001)。总之,本研究的结果表明OPRK1启动子的甲基化有助于药物成瘾的病理生理。

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