Pharmazentrum Frankfurt, Zentrum für Arzneimittelforschung Entwicklung und Sicherheit (ZAFES), Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
Fraunhofer Institute for Molecular Biology and Applied Ecology, Project Group for Translational Medicine &Pharmacology, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany.
Nat Rev Neurol. 2017 Jul;13(7):434-447. doi: 10.1038/nrneurol.2017.68. Epub 2017 May 26.
More than 20% of adults worldwide experience different types of chronic pain, which are frequently associated with several comorbidities and a decrease in quality of life. Several approved painkillers are available, but current analgesics are often hampered by insufficient efficacy and/or severe adverse effects. Consequently, novel strategies for safe, highly efficacious treatments are highly desirable, particularly for chronic pain. Epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs (miRNAs) strongly affect the regulation of gene expression, potentially for long periods over years or even generations, and have been associated with pathophysiological pain. Several studies, mostly in animals, revealed that inhibitors of DNA methylation, activators and inhibitors of histone modification and modulators of miRNAs reverse a number of pathological changes in the pain epigenome, which are associated with altered expression of pain-relevant genes. This epigenetic modulation might then reduce the nociceptive response and provide novel therapeutic options for analgesic therapy of chronic pain states. However, a number of challenges, such as nonspecific effects and poor delivery to target cells and tissues, hinder the rapid development of such analgesics. In this Review, we critically summarize data on epigenetics and pain, focusing on challenges in clinical development as well as possible new approaches to the drug modulation of the pain epigenome.
全世界超过 20%的成年人患有不同类型的慢性疼痛，这些疼痛常常与多种合并症和生活质量下降有关。有几种经过批准的止痛药，但目前的镇痛药往往因疗效不足和/或严重的不良反应而受到限制。因此，人们非常希望开发出安全、高效的新型治疗策略，尤其是针对慢性疼痛。表观遗传机制，如 DNA 甲基化、组蛋白修饰和 microRNAs（miRNAs），强烈影响基因表达的调控，可能在数年甚至数代的时间内持续很长时间，并与病理性疼痛有关。多项主要在动物身上进行的研究表明，DNA 甲基化抑制剂、组蛋白修饰激活剂和抑制剂以及 miRNAs 调节剂可逆转疼痛表观基因组中的许多病理性变化，这些变化与疼痛相关基因的表达改变有关。这种表观遗传调节可能会降低伤害性反应，并为慢性疼痛状态的镇痛治疗提供新的治疗选择。然而，一些挑战，如非特异性作用和对靶细胞和组织的递送效果差，阻碍了这些镇痛药的快速开发。在这篇综述中，我们批判性地总结了与表观遗传学和疼痛相关的数据，重点讨论了临床开发中的挑战以及药物调节疼痛表观基因组的可能新方法。
