Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma

Abstract

Accumulating evidence suggests that epigenetic alterations lie behind the induction and maintenance of neuropathic pain. Neuropathic pain is usually a chronic condition caused by a lesion, or pathological change, within the nervous system. Neuropathic pain appears frequently after nerve and spinal cord injuries or diseases, producing a debilitation of the patient and a decrease of the quality of life. At the cellular level, neuropathic pain is the result of neuronal plasticity shaped by an increase in the sensitivity and excitability of sensory neurons of the central and peripheral nervous system. One of the mechanisms thought to contribute to hyperexcitability and therefore to the ontogeny of neuropathic pain is the altered expression, trafficking, and functioning of receptors and ion channels expressed by primary sensory neurons. Besides, neuronal and glial cells, such as microglia and astrocytes, together with blood borne macrophages, play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as pro-inflammatory cytokines and chemokines, which enhance neuronal excitability. Altered gene expression of neuronal receptors, ion channels, and pro-inflammatory cytokines and chemokines, have been associated to epigenetic adaptations of the injured tissue. Within this review, we discuss the involvement of these epigenetic changes, including histone modifications, DNA methylation, non-coding RNAs, and alteration of chromatin modifiers, that have been shown to trigger modification of nociception after neural lesions. In particular, the function on these processes of EZH2, JMJD3, MeCP2, several histone deacetylases (HDACs) and histone acetyl transferases (HATs), G9a, DNMT, REST and diverse non-coding RNAs, are described. Despite the effort on developing new therapies, current treatments have only produced limited relief of this pain in a portion of patients. Thus, the present review aims to contribute to find novel targets for chronic neuropathic pain treatment.

Keywords: epigenetic enzymes; inflammation; neuronal hyperexcitability; neuropathic pain; traumatic injury.

FIGURE 1

Traumatic injuries of the nervous system induce epigenetic alterations triggering inflammation and neuropathic pain. Neural injuries produce an increase of the expression of several epigenetic enzyme in microglia, macrophages, astrocytes, endothelial cells, and neurons of the DRG after neural injuries. These enzymes alter the promoter state of several pro-inflammatory neuromodulators inducing their expression. Enhanced gene expression of these cytokines, chemokines, and neurotrophic factors, produce inflammation, and consequent neuropathic pain. BET, bromodomain and extra terminal domain; DNMTs, DNA methyltransferases; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; HAT, histone acetyltransferase enzymes; HDAC, histone deacetylases; JMJD3, jumonji domain containing 3; MeCP2, methyl-CpG-binding protein 2.

FIGURE 2

Traumatic injuries of the nervous system induce gene expression alteration in neurons triggering hyperexcitability and neuropathic pain. During control conditions, the promoter state of genes codifying for ion channels, receptors and other important neuronal genes allow the recruitment of transcription factors, and thus gene expression. After a traumatic injury of the nervous system, there is an increased expression of methyltransferases (G9a, histone-lysine N-methyltransferase; DNMT3a, DNA methyltransferase a), and the repressor complex REST (RE1-silencing transcription factor), with decrease H3K4 methylation and increase H3K9 methylation. This alteration of the promoter state does not allow transcription factor recruitment and there is silencing of several neuronal genes. De-balanced expression of ion channel, receptors, transporters, and other neuronal genes triggers neuronal hyperexcitability and consequent neuropathic pain.