DNA Methylation: A Target in Neuropathic Pain

Abstract

Neuropathic pain (NP), caused by an injury or a disease affecting the somatosensory nervous system of the central and peripheral nervous systems, has become a global health concern. Recent studies have demonstrated that epigenetic mechanisms are among those that underlie NP; thus, elucidating the molecular mechanism of DNA methylation is crucial to discovering new therapeutic methods for NP. In this review, we first briefly discuss DNA methylation, demethylation, and the associated key enzymes, such as methylases and demethylases. We then discuss the relationship between NP and DNA methylation, focusing on DNA methyltransferases including methyl-CpG-binding domain (MBD) family proteins and ten-eleven translocation (TET) enzymes. Based on experimental results of neuralgia in animal models, the mechanism of DNA methylation-related neuralgia is summarized, and useful targets for early drug intervention in NP are discussed.

Keywords: DNA methylation; epigenetic; gene suppression; neuropathic pain; treatment.

Figure 1

DNA methylation in the mechanism of neuropathic pain (NP). The dorsal root ganglion (DRG) and spinal cord produce glial cell responses, stimulating inflammatory cytokines, nerve growth factors, gene expression, and ion channels under the environment of peripheral afferent fiber injury. CCI, chronic constriction injury; SNL, spinal nerve ligation; SNI, spared nerve injury; DRG, dorsal root ganglion; NGF, nerve growth factors; Na⁺, Na⁺ channels; K⁺, K⁺ channels; Ca⁺, Ca⁺ channels.

Figure 2

DNA methylation and demethylation: (A) TF and RNAPII bind to the promoter region of the gene, activating transcription at unmethylated promoters. (B) CpG island methylation is mediated by DNA methyltransferases and induces DNA methylation through MBD proteins. (C) Transcription factors recruit TET enzymes to specific sites for regulating local DNA demethylation.TF, transcription factor; RNAPII, RNA polymerase II; TSS, transcriptional start site; DNMT, DNA-methyltransferases; MBD, methyl-CpG-binding domain; TET, ten-eleven translocation.