Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain

Abstract

Peripheral nerve injury causes neuropathic pain, which is characterized by the paradoxical sensations of positive and negative symptoms. Clinically, negative signs are frequently observed; however, their underlying molecular mechanisms are largely unknown. Dysfunction of C-fibers is assumed to underlie negative symptoms and is accompanied by long-lasting downregulation of Na v 1.8 sodium channel and -opioid receptor (MOP) in the dorsal root ganglion (DRG). In the present study, we found that nerve injury upregulates neuronrestrictive silencer factor (NRSF) expression in the DRG neurons mediated through epigenetic mechanisms. In addition, chromatin immunoprecipitation analysis revealed that nerve injury promotes NRSF binding to the neuron-restrictive silencer element within MOP and Na v 1.8 genes, thereby causing epigenetic silencing. Furthermore, NRSF knockdown significantly blocked nerve injury-induced downregulations of MOP and Na v 1.8 gene expressions, C-fiber hypoesthesia, and the losses of peripheral morphine analgesia and Na v 1.8-selective blocker-induced hypoesthesia. Together, these data suggest that NRSF causes pathological and pharmacological dysfunction of C-fibers, which underlies the negative symptoms in neuropathic pain.

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

“…Transcription factors, such as repressor element 1-silencing transcription factor may bind to the Oprm1 promoter to inhibit Oprm1 expression through histone deacetylases. Both histone deacetylase inhibi- tors and repressor element 1-silencing transcription factor knockdown can increase MOR expression levels and the morphine analgesic effect reduced by nerve injury (12,48), supporting this possibility. Because G9a is essential for silencing of repressor element 1-silencing transcription factor-regulated genes (49) and can regulate polycomb repressive complex 2 on histone H3K9 to mediate gene silencing (38), it is possible that G9a forms a repressive complex with repressor element 1-silencing transcription factor, histone deacetylases, DNA methyltransferases, and EZH2 at the Oprm1 promoter in the injured DRG.…”

“…MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10). Peripheral nerve injury reduces the expression level of MORs in the dorsal root ganglion (DRG), contributing to the loss of opioid analgesic efficacy in neuropathic pain (6,11,12). However, the epigenetic mechanisms by which nerve injury leads to diminished MOR expression in the DRG remain unclear.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…However, insufficient dosing or injection volume may have accounted for the absence of antinociception in these studies (Aley and Levine, 2002;Rashid et al, 2004;Whiteside et al, 2004). Suppression of opioid receptor expression by a silencer factor has also been suggested in PSL (Uchida et al, 2010). Although -receptors were down-regulated in DRG after SNL (Kohno et al, 2005), morphine injected into the ipsilateral paw or systemic loperamide still exerted antinociceptive effects (Pertovaara and Wei, 2001;Guan et al, 2008).…”

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury

“…Several regions of the nociceptive pathway, including the anterior cingulate cortex (ACC), hippocampus, spinal dorsal horn (SDH) and dorsal root ganglion (DRG), are involved in the development and maintenance of neuropathic pain (4)(5)(6)(7)(8)(9). Several recent studies have shown that peripheral and central sensitization are associated with global changes in gene expression in different regions of the pain transmission pathway, and that these changes may be part of the mechanisms behind neuropathic pain (10)(11)(12)(13). In order to elucidate the molecular mechanisms underlying neuropathic pain, it is essential to determine how gene expression patterns are altered by nerve injuries and how these alterations lead to the development and maintenance of chronic pain.…”