Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain
Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain
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DOI：
10.1016/j.pain.2012.06.011
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发表时间：
2013-01-01
期刊：
影响因子：
7.4
通讯作者：
Loetsch, Joern
中科院分区：
文献类型：
--
作者：
Doehring, Alexandra;Oertel, Bruno Georg;Loetsch, Joern
环境引起的染色体变化不会改变DNA序列，但通过改变基因转录而引起表型变化，这些变化被概括为表观遗传学。一个主要的表观遗传机制是富含CpG的DNA岛上的甲基化或去甲基化。由药物引发的DNA甲基化在很大程度上尚未探索治疗后果。在这里，我们报告了与匹配的健康对照组相比，美沙酮替代的前阿片成瘾者白细胞中编码Mu-阿片受体的OPRM1基因中CpG富集岛和全局甲基化位点(LINE-1)的甲基化增加。与非阿片类药物治疗的疼痛患者相比，与慢性阿片类药物暴露相关的更高的DNA甲基化在阿片类药物治疗的独立队列中再现。这表明阿片类药物可能会刺激DNA甲基化。OPRM1甲基化对Mu-阿片受体转录没有直接影响，也与阿片类药物剂量要求无关。然而，LINE-1的全球DNA甲基化与慢性疼痛的增加显著相关。这表明对仍未明确的致病基因产物的转录有抑制作用。这进一步意味着阿片类药物可能与全基因组DNA甲基化增加有因果关系，尽管目前没有直接证据表明这一点。这对疼痛有表型影响，并可能为阿片类药物诱导的痛敏提供一种新的表观遗传学相关机制。结果表明，阿片类镇痛剂对患者的表观基因组有潜在的影响。他们强调需要可靠和成本效益高的筛选工具，并可能意味着在人工表达系统中对先导化合物进行高通量筛选可能不会提供识别新止痛药的最佳工具。(C)2012年国际疼痛研究协会。爱思唯尔出版公司版权所有。
Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences. Here we report increased methylation at a CpG rich island in the OPRM1 gene coding for mu-opioid receptors and at a global methylation site (LINE-1) in leukocytes of methadone-substituted former opiate addicts compared with matched healthy controls. Higher DNA methylation associated with chronic opioid exposure was reproduced in an independent cohort of opioid-treated as compared to non-opioid-treated pain patients. This suggests that opioids may stimulate DNA methylation. The OPRM1 methylation had no immediate effect on mu-opioid receptor transcription and was not associated with opioid dosing requirements. However, the global DNA methylation at LINE-1 was significantly correlated with increased chronic pain. This suggests inhibitory effects on the transcription of still unspecified nocifensive gene products. It further implies that opioids may be causally associated with increased genome-wide DNA methylation, although currently there is no direct evidence of this. This has phenotypic consequences for pain and may provide a new, epigenetics-associated mechanism of opioid-induced hyperalgesia. The results indicate a potential influence of opioid analgesics on the patients' epigenome. They emphasize the need for reliable and cost-effective screening tools and may imply that high-throughput screening for lead compounds in artificial expression systems may not provide the best tools for identifying new pain medications. (C) 2012 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.