Abstract
Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increases in primary sensory neurons in injured dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. In injected DRG, mimicking nerve trauma-induced C/EBPβ upregulation increased TLR7 levels, augmented responses to cold/thermal/mechanical stimuli, and caused ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in injured primary sensory neurons.
Highlights
Neuropathic pain refers to chronic pain resulting from central or peripheral nervous system (CNS, PNS) disease or injury, which poses a massive challenge to physicians due to poor response to conventional pain treatments
Before we explored the participation of CCAAT/enhancer-binding protein-β (C/EBPβ) in SNLinduced toll-like receptor 7 (TLR7) transcriptional activity in injured dorsal root ganglion (DRG), the change in C/EBPβ level was examined in two regions associated with pain, including DRG, and spinal cord, following spinal nerve ligation (SNL) or sham surgery
Peripheral neuropathic pain primarily resulted from peripheral nerve injury leading to DRG neurons with axotomized and uninterrupted fibers, which may conduct in the corresponding receptive fields
Summary
Neuropathic pain refers to chronic pain resulting from central or peripheral nervous system (CNS, PNS) disease or injury, which poses a massive challenge to physicians due to poor response to conventional pain treatments. About 3.3–17.9% of the USA and European population suffers from neuropathic pain [1]. It is identified based on persistent pain of spontaneous onset, cold/thermal hyperalgesia, spasmodic burning pain, and allodynia. Some treatments are available to treat neuropathic pain, like non-steroidal antiinflammatory drugs (NSAIDs), opioids, antidepressants, and anti-convulsants [1,2,3]. Many cases do not achieve sufficient pain relief using the existing therapeutics since they mostly lack specificity to neuropathic pain [1, 3]. Discerning the underlying mechanisms of neuropathic pain could provide new and more efficient therapeutic strategies for treating neuropathic pain
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