Abstract
BackgroundChronic pain usually accompanied by tissue damage and inflammation. However, the pathogenesis of chronic pain remains unclear.MethodsWe investigated the role of nerve growth factor (NGF) in chronic inflammatory pain induced by complete Freund’s adjuvant (CFA), explored the methylation status of CpG islands in the promoter region of the NGF gene, and clarified the function and mechanism of C/EBPα-NGF signaling pathway from epigenetic perspective in the chronic inflammatory pain model.ResultsCFA induced significant hyperalgesia and continuous upregulation of NGF mRNA and protein levels in the L4–6 dorsal root ganglions (DRGs) in rats. Hypomethylation of CpG islands occurred in the NGF gene promoter region after CFA treatment. At the same time, the miR-29b expression level was significantly increased, while the DNA methyltransferase 3b (DNMT3b) level reduced significantly. Moreover, CFA treatment promoted binding of C/EBPα to the NGF gene promoter region and C/EBPα siRNA treatment obviously decreased expression of NGF levels and also alleviate inflammatory hyperalgesia significantly in rats.ConclusionCollectively, the results indicated that CFA leads to the upregulation of miR-29b level, which represses the expression of DNMT3b, enhances the demethylation of the NGF gene promoter region, and promotes the binding of C/EBPα with the NGF gene promoter, thus results in the upregulation of NGF gene expression and maintenance of chronic inflammatory pain.
Highlights
Chronic pain usually accompanied by tissue damage and inflammation
complete Freund’s adjuvant (CFA)-induced inflammatory pain model of rats To observe the CFA-induced inflammatory pain behavior in rats, we found injection of CFA produced a significant reduction in paw withdrawal threshold (PWT) starting at 1 day after injection (**P < 0.01, Fig. 1a)
Hypomethylation of CpG islands in the nerve growth factor (NGF) gene promoter after CFA treatment To explore whether DNA hypomethylation leads to the upregulation of NGF, we detected the methylation status in the NGF gene promoter region by using the method of methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) assays
Summary
The pathogenesis of chronic pain remains unclear. Most scholars believe that tissue damage or inflammation leads to increased release of multiple inflammatory factors or pain-related genes, and this may be an important factor for the formation and development of chronic pain [1,2,3], but the pathogenesis of chronic pain remains unclear. Chronic pain may be involved in epigenetic changes of many coding or noncoding genes. Many studies showed that pain modulation is closely related to epigenetic regulation, especially DNA methylation, which plays an important role in the modulation of inflammation or tissue-damaging pain [5,6,7]. Further study of the epigenetic changes of related genes in pain modulation may have important clinical significance for the treatment of inflammatory pain, especially chronic pain
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