Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
Biochem Pharmacol. 2024 Sep;227:116427. doi: 10.1016/j.bcp.2024.116427. Epub 2024 Jul 14.
Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A-Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics.
神经病理性疼痛是一种普遍且难治的疾病，但其发病机制仍不清楚。尽管 NMDA 受体的必需亚基 NR1 长期以来一直被认为在伤害性传递中起着关键作用，但它在突触前刺激中的作用尚未完全阐明。转录因子可以调节促伤害性和镇痛因子的表达。我们的研究表明，转录因子 TFAP2A 在脊神经结扎（SNL）后背根神经节（DRG）神经元、卫星胶质细胞（SGC）和雪旺细胞中上调。SNL 后立即或 7 天鞘内注射靶向 Tfap2a 的 siRNA 可有效缓解 SNL 诱导的痛觉过敏，并降低 Tfap2a 表达水平。生物信息学分析表明，TFAP2A 可能调节编码 NR1 的 Grin1 基因的表达。双荧光素酶报告基因检测证实了 TFAP2A 对 Grin1 表达的正向调节作用。值得注意的是，Tfap2a 和 Grin1 均在原代 SGC 中表达，并被脂多糖上调。DRG 中 Tfap2a 敲低后 Grin1 的表达也下调。此外，SNL 后立即或 7 天鞘内注射靶向 Grin1 的 siRNA 可有效缓解 SNL 诱导的机械性痛觉过敏和热痛觉过敏。最后，鞘内注射 Tfap2a siRNA 可缓解 SNL 诱导的神经元敏感性增加，而用 Tfap2a siRNA 孵育原代 SGC 可降低 NMDA 诱导的促炎细胞因子的上调。总之，我们的研究揭示了 TFAP2A-Grin1 在调节周围胶质细胞神经病理性疼痛中的作用，为开发新型镇痛药提供了新策略。
