Painful diabetic neuropathy commonly affects the peripheral nervous system in individuals with diabetes. However, the pathological processes and mechanisms underlying diabetic neuropathic pain remain unclear. We aimed to identify the overall profiles and screen for genes potentially involved in pain mechanisms using transcriptome analysis of the dorsal root ganglion of diabetic mice treated with streptozotocin (STZ). Using RNA sequencing, we identified differentially expressed genes (DEGs) between streptozotocin-treated diabetic mice and controls, focusing on altered GABAergic neuron-related genes and inflammatory pathways. Behavioral and molecular analyses revealed a marked reduction in GABAergic neuronal markers (GAD65, GAD67, VGAT) and increased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in the diabetic group compared to controls. Intrathecal administration of lentiviral vectors expressing transcription factors Ascl1 and Lhx6 reversed pain hypersensitivity and restored normal expression of GABAergic genes and inflammatory mediators. Protein-protein interaction (PPI) network analysis revealed five key proteins influenced by Ascl1 and Lhx6 treatment, including those in the JunD/FosB/C-fos signaling pathway. These findings suggest that Ascl1 and Lhx6 mitigate diabetic neuropathic pain by modulating GABAergic neuronal function, pro-inflammatory responses, and pain-related channels (TRPV1, Nav1.7). These results provide a basis for developing transcription factor-based therapies targeting GABAergic neurons for diabetic neuropathic pain relief.

中文翻译：

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链脲佐菌素-糖尿病小鼠 Ascl1 和 Lhx6 依赖性 GABA 能神经元功能对疼痛敏感性的调节。


疼痛性糖尿病神经病变通常会影响糖尿病患者的周围神经系统。然而，糖尿病神经性疼痛的病理过程和机制仍不清楚。我们旨在通过对链脲佐菌素 （STZ） 治疗的糖尿病小鼠背根神经节进行转录组分析，确定总体概况并筛选可能参与疼痛机制的基因。使用 RNA 测序，我们鉴定了链脲佐菌素处理的糖尿病小鼠和对照之间的差异表达基因 （DEG），重点关注改变的 GABA 能神经元相关基因和炎症通路。行为和分子分析显示，与对照组相比，糖尿病组的 GABA 能神经元标志物 （GAD65、GAD67、VGAT） 显著减少，促炎细胞因子 （TNF-α、IL-1β、IL-6） 增加。鞘内施用表达转录因子 Ascl1 和 Lhx6 的慢病毒载体可逆转疼痛超敏反应并恢复 GABA 能基因和炎症介质的正常表达。蛋白-蛋白相互作用 （PPI） 网络分析揭示了受 Ascl1 和 Lhx6 处理影响的 5 种关键蛋白，包括 JunD/FosB/C-fos 信号通路中的蛋白。这些发现表明，Ascl1 和 Lhx6 通过调节 GABA 能神经元功能、促炎反应和疼痛相关通道 （TRPV1、Nav1.7） 来减轻糖尿病神经性疼痛。这些结果为开发靶向 GABA 能神经元的基于转录因子的疗法以缓解糖尿病神经性疼痛提供了基础。