Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain.
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 mu-opioid receptor (MOP) in the dorsal root ganglion (DRG). In the present study, we found that nerve injury upregulates neuron-restrictive 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.
Uchida
Hitoshi
H
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan.
Ma
Lin
L
Ueda
Hiroshi
H
D000107:Acetylation; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D062559:NAV1.8 Voltage-Gated Sodium Channel; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D011485:Protein Binding; D017450:Receptors, Opioid, mu / Q000096:biosynthesis / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D012584:Sciatic Nerve / Q000293:injuries; D037941:Silencer Elements, Transcriptional; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
D000701:Analgesics, Opioid; D006657:Histones; D009020:Morphine; D062559:NAV1.8 Voltage-Gated Sodium Channel; D017450:Receptors, Opioid, mu; D012097:Repressor Proteins; D015222:Sodium Channels; D000099229:RE1-Silencing Transcription Factor; C568318:Scn10a protein, mouse