Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China.
Int J Mol Med. 2018 Jul;42(1):633-642. doi: 10.3892/ijmm.2018.3613. Epub 2018 Apr 3.
Treatment of neuropathic pain (NPP) continues to be a major challenge, and the underlying mechanisms remain to be elucidated. Previous studies have demonstrated that histone methylation is important in synaptic plasticity of the nervous system and may affect nuclear factor‑κB (NF‑κB) signaling through epigenetic mechanisms. The present study aimed to investigate the role of Jumonji C domain 6 (JMJD6), a histone demethylase, in a chronic constriction injury (CCI) model of NPP. On the third day post‑CCI surgery, a JMJD6 overexpressing lentiviral vector (LV‑JMJD6) was intrathecally injected in the rats. Mechanical withdrawal threshold and thermal withdrawal latency were assessed prior surgery and on days 3, 7, 10 and 14 post‑CCI. The results showed that intrathecal injection with the LV‑JMJD6 attenuated CCI‑induced pain facilitation. The expression of JMJD6 was lower following CCI surgery, and its expression was significantly increased following intrathecal injection with LV‑JMJD6, compared with levels in normal saline (NS)‑ and negative control lentiviral vector (NC)‑treated rats. The expression of spinal NF‑κB phosphorylated (p‑)p65 subunit and its downstream pain‑associated effectors, including interleukin 1β (IL‑1β), tumor necrosis factor‑α (TNF‑α) and vascular endothelial growth factor (VEGF), were increased following CCI surgery. Intrathecal injection with LV‑JMJD6 suppressed activation of the p‑p65 subunit in CCI rats. In addition, expression levels of its downstream effectors IL‑1β, TNF‑α and VEGF were attenuated by intrathecal treatment with LV‑JMJD6, compared with those in the NS‑ and NC‑treated CCI rats. Furthermore, the JMJD6‑ and p65‑immunoreactive cells overlapped in the spinal dorsal horn, however, co‑immunoprecipitation showed that JMJD6 and the NF‑κB p65 subunit did not directly interact, indicating other functional connections may exist between these factors following CCI surgery. Collectively, these findings indicated an important mechanism underlying the pathogenesis of NPP. JMJD6 may exert its therapeutic function in NPP by regulating NF‑κB following CCI.
治疗神经性疼痛（NPP）仍然是一个主要挑战，其潜在机制仍有待阐明。先前的研究表明，组蛋白甲基化在神经系统的突触可塑性中很重要，并且可能通过表观遗传机制影响核因子-κB（NF-κB）信号。本研究旨在探讨组蛋白去甲基化酶 Jumonji C 结构域 6（JMJD6）在慢性缩窄性损伤（CCI）NPP 模型中的作用。在 CCI 手术后第 3 天，鞘内注射 JMJD6 过表达慢病毒载体（LV-JMJD6）。在手术前和 CCI 手术后第 3、7、10 和 14 天评估机械性撤回避触阈值和热撤回避潜伏期。结果显示，鞘内注射 LV-JMJD6 可减轻 CCI 引起的疼痛加剧。CCI 手术后 JMJD6 的表达降低，而鞘内注射 LV-JMJD6 后其表达明显高于生理盐水（NS）和阴性对照慢病毒载体（NC）处理的大鼠。CCI 手术后脊髓 NF-κB 磷酸化（p）p65 亚基及其下游痛相关效应物，包括白细胞介素 1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和血管内皮生长因子（VEGF）的表达增加。鞘内注射 LV-JMJD6 抑制了 CCI 大鼠中 p-p65 亚基的激活。此外，与 NS 和 NC 处理的 CCI 大鼠相比，鞘内注射 LV-JMJD6 可减轻其下游效应物 IL-1β、TNF-α 和 VEGF 的表达水平。此外，在脊髓背角中，JMJD6 和 p65 免疫反应性细胞重叠，但共免疫沉淀显示 JMJD6 和 NF-κB p65 亚基不直接相互作用，这表明 CCI 手术后这些因素之间可能存在其他功能联系。总之，这些发现表明了 NPP 发病机制的一个重要机制。JMJD6 可能通过 CCI 后调节 NF-κB 在 NPP 中发挥治疗作用。
