Abstract
BackgroundStudies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG). However, the molecular mechanisms underlying Nav1.6 upregulation were not reported yet.MethodsThe paw withdrawal threshold was measured in the rodents following lumbar 5 ventral root transection (L5-VRT). Then qPCR, western blotting, immunoprecipitation, immunohistochemistry, and chromatin immunoprecipitation assays were performed to explore the molecular mechanisms in vivo and in vitro.ResultsWe found that the levels of Nav1.6 and phosphorylated STAT3 were significantly increased in DRG neurons following L5-VRT, and TNF-α incubation also upregulated the Nav1.6 expression in cultured DRG neurons. Furthermore, immunoprecipitation and chromatin immunoprecipitation assays demonstrated that L5-VRT increased the binding of STAT3 to the Scn8a (encoding Nav1.6) promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of Scn8a by increasing histone H4 acetylation in Scn8a promoter in DRG. Importantly, intraperitoneal injection of the TNF-α inhibitor thalidomide reduced the phosphorylation of STAT3 and decreased the recruitment of STAT3 and histone H4 hyperacetylation in the Scn8a promoter, thus subsequently attenuating Nav1.6 upregulation in DRG neurons and mechanical allodynia induced by L5-VRT.ConclusionThese results suggested a new mechanism for Nav1.6 upregulation involving TNF-α/STAT3 pathway activation and subsequent STAT3-mediated histone H4 hyperacetylation in the Scn8a promoter region in DRG, which contributed to L5-VRT-induced neuropathic pain.
Highlights
Studies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG)
Upregulation of Nav1.6 in DRG was involved in mechanical allodynia induced by lumbar 5 ventral root transection (L5-VRT) Consistent with our previous study [19, 21], the results showed that L5-VRT markedly decreased the withdrawal threshold compared to the sham group (Fig. 1a)
Increased Tumor necrosis factor-α (TNF-α) contributed to Nav1.6 upregulation and mechanical allodynia induced by L5-VRT we found that L5-VRT markedly induced the increase of TNF-α in DRG (Fig. 2a)
Summary
Studies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG). It is well known that these VGSCs play the critical roles in regulating the excitability and firing pattern of neurons and contribute to the neuropathic pain. Isoforms Nav1.7, Nav1.8, and Nav1.9 have been linked with pain disorders by regulating the action potential and firing properties of dorsal root ganglion (DRG) neurons [5, 6]. Ding et al Journal of Neuroinflammation (2019) 16:29 that upregulation of Nav1.6 increased the DRG neuron excitability and contributed to the development of neuropathic pain [7]. The mechanism underlying the increased expression of Nav1.6 is not reported in neuropathic pain induced by nerve injury
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