HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain.
HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain.
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mPFC 中的 HMGB1 控制神经性疼痛中的共病焦虑
DOI：
10.1186/s10194-022-01475-z
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发表时间：
2022-08-16
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神经炎症是否会导致神经性疼痛中的共病情绪障碍仍然是难以捉摸的。在这里，我们调查的作用，高迁移率族蛋白1（HMGB 1），促炎细胞因子，在内侧前额叶皮层（mPFC）的焦虑合并症的神经病理性疼痛。神经性疼痛通过部分横断小鼠眶下神经（p-IONX）或部分坐骨神经结扎（PSL）诱导，并通过测量对机械和热刺激的伤害性阈值来评估。通过高架十字迷宫、光暗盒和旷场实验评估大鼠的类迷宫行为。条件性位置偏爱实验检测厌恶或反厌恶效应。神经元活性通过单单位和膜片钳记录进行评价。通过光遗传学选择性抑制mPFC锥体神经元，进一步检查mPFC锥体神经元对焦虑的贡献。免疫组化和蛋白质印迹法检测HMGB 1的表达。通过脑内或腹腔注射抗HMGB 1单克隆抗体（mAb）实现HMGB 1的拮抗。p-IONX后比PSL后更早地出现了类似行为。HMGB 1表达上调mPFC暂时平行于焦虑发作，而不是在其他地区与焦虑。HMGB 1的表达上调及其从细胞核到细胞质的易位主要发生在mPFC的神经元，并伴有小胶质细胞和星形胶质细胞的激活。在p-IONX或PSL后的早期和晚期阶段，将抗HMGB 1 mAb输注到mPFC中可减轻焦虑样行为和厌恶，而不改变疼痛敏感性，而将外源性ds-HMGB 1（HMGB 1的促炎形式）局部输注到mPFC中可诱导幼稚小鼠的焦虑和厌恶，但不引起疼痛敏感性。除了同时逆转已建立的疼痛敏感化和焦虑外，腹膜内注射抗HMGB 1 mAb可减少HMGB 1上调，并抑制p-IONX后mPFC中第2/3层锥体神经元的过度兴奋。此外，mPFC锥体神经元的光遗传学抑制减轻了p-IONX小鼠的焦虑。这些结果表明，mPFC中的HMGB 1通过增加第2/3层锥体神经元的兴奋性来驱动和维持神经性疼痛中的焦虑共病，并证明HMGB 1的拮抗作用，例如，通过单克隆抗体中和，作为一种有前途的治疗策略，神经性疼痛与焦虑共病。在线版本包含补充材料，可通过10.1186/s10194-022-01475-z获得。
Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity. The online version contains supplementary material available at 10.1186/s10194-022-01475-z.
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