BDNF-TrkB-KCC2 通路在臂丛神经撕脱伤后神经病理性疼痛中的作用。
Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion.
机构信息
Department of Hand Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
Orthopaedic Department, Children's Hospital of Hebei Province, Shijiazhuang, China.
出版信息
Brain Behav. 2022 Mar;12(3):e2464. doi: 10.1002/brb3.2464. Epub 2022 Feb 1.
INTRODUCTION
Brachial plexus avulsion significantly increased brain-derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain caused by BPA injury. We hypothesized that activation of BDNF-TrkB may inhibit neuronal excitability by downregulating KCC2 to maintain a high intracellular Cl-concentration. We established a neuropathic pain rat model by avulsion of the lower trunk brachial plexus, and investigated the effects of the TrkB-specific antibody K-252a on the expression of BDNF, TrkB, and KCC2.
METHODS
We randomly divided 40 male SD rats into four groups. In the brachial plexus avulsion group, C8-T1 roots were avulsed from the spinal cord at the lower trunk level. In the K252a group, 5uL K252a was applied intrathecally daily for three days after avulsion. In the sham surgery group, expose only and without damage. The control group did not undergo any treatment. Mechanical hyperalgesia and cold allodynia were analyzed by electronic pain measuring instrument and acetone spray method at different time points on days 1, 3, 7, 10, 14, and 21 after surgery. At 21 days after surgery, the expression of BDNF and TrkB in dorsal horn neurons and GFAP in astrocytes were detected by immunohistochemistry at the C5-T1 segment of the spinal cord. The expression levels of BDNF, TrkB, and KCC2 in the C5-T1 spinal cord were measured by Western Blot at 7 and 21 days.
RESULTS
Mechanical hyperalgesia and cold allodynia were significantly reduced in the K252a group compared with the brachial plexus avulsion group. Compared with the BPA group, BDNF, TrkB and GFAP were significantly decreased in the K252a group at 21 days after treatment by immunohistochemical test. In the WB test, the expressions of BDNF and TrkB in the K252a group were quantitatively detected to be decreased, while the expression of KCC2 was increased, which was obvious at 7 and 21 days.
CONCLUSION
BDNF-TrkB-KCC2 pathway can significantly relieve neuropathic pain after BPA, and is a potential target for the treatment of neuropathic pain.
简介
臂丛神经撕脱伤显著增加了脊髓中脑源性神经营养因子（BDNF）的释放。在这里，我们研究了 BDNF-TrkB-KCC2 通路在 BPA 损伤引起的神经病理性疼痛中的作用。我们假设 BDNF-TrkB 的激活可能通过下调 KCC2 来抑制神经元兴奋性，从而维持高细胞内 Cl-浓度。我们通过撕脱下位干臂丛神经根建立了神经病理性疼痛大鼠模型，并研究了 TrkB 特异性抗体 K-252a 对 BDNF、TrkB 和 KCC2 表达的影响。
方法
我们将 40 只雄性 SD 大鼠随机分为四组。在臂丛神经撕脱组中，将 C8-T1 根从下位干脊髓撕脱。在 K252a 组中，撕脱后每日鞘内给予 5μL K252a 共 3 天。在假手术组中，仅暴露而不损伤。对照组不进行任何治疗。术后第 1、3、7、10、14 和 21 天，采用电子疼痛测量仪和丙酮喷雾法分析机械性痛觉过敏和冷感觉过敏。术后第 21 天，采用免疫组织化学法检测脊髓 C5-T1 节段背角神经元 BDNF 和 TrkB 的表达以及星形胶质细胞 GFAP 的表达。采用 Western blot 法检测 C5-T1 脊髓 BDNF、TrkB 和 KCC2 的表达水平，分别于术后第 7 天和第 21 天进行检测。
结果
与臂丛神经撕脱组相比，K252a 组的机械性痛觉过敏和冷感觉过敏明显减轻。与 BPA 组相比，K252a 组治疗后第 21 天，免疫组织化学检测 BDNF、TrkB 和 GFAP 明显减少。在 WB 试验中，定量检测 K252a 组 BDNF 和 TrkB 的表达减少，而 KCC2 的表达增加，7 天和 21 天均明显增加。
结论
BDNF-TrkB-KCC2 通路可显著缓解 BPA 后神经病理性疼痛，是治疗神经病理性疼痛的潜在靶点。
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