外侧臂旁核在触诱发痛时空控制中的作用及其机制

机械触诱发痛（mechanical allodynia），简称触诱发痛，指的是由正常情况下非痛的轻触刺激所诱发的异常疼痛现象，它是炎症性和神经病理性疼痛的典型症状。触诱发痛分为两种类型，一种是静态（点状）触诱发痛，是由如von Frey纤维丝等对皮肤表面施加稳定的轻触压力引起；另外一种是动态触诱发痛，是由如画笔等轻轻地划过皮肤的表面引起的。触诱发痛对吗啡等阿片类镇痛药相对不敏感，属于顽固性和难治性的异常疼痛，严重影响患者的日常起居和生活质量。在少数患者中，局部炎症或神经损伤可能会引起长时程、全身性的机械痛觉敏化（触诱发痛），而对于大多数患者来说，疼痛局限于损伤侧且持续时间较短。然而，控制机械痛觉敏化持续时间和侧性的神经环路机制，特别是侧性控制，目前仍知之甚少。

本研究工作主要在各种基因工程的小鼠上，应用行为学测试和脊髓及脑片电生理记录，结合病毒、化学遗传学、脑立体定位、免疫组化和原位杂交等技术聚焦解析脑干外侧臂旁核(lateral parabrachial nucleus，lPBN)不同类型神经元在外周炎症或神经损伤引起的机械痛觉敏化中的作用及其神经环路机制。

我们的研究发现，化学损毁外周炎症或神经损伤对侧（而非同侧）的lPBN后，1）足底注射辣椒素或福尔马林等伤害性物质引起的触诱发痛的时程显著延长（从几个小时到至少两周时间）；2）外周神经损伤（SNI模型）引起的触诱发痛从单侧（unilateral）变成了双侧(bilateral)；3）脊髓背角双侧的触诱发痛“门控”打开。以上研究结果提示，lPBN在外周炎症或神经损伤引起的机械痛觉敏化的持续时间和敏化范围的调控中起着至关重要的作用。该部分内容对应本论文第3章节。

本论文第4，5和6章节聚焦解析外侧臂旁核控制机械痛觉敏化时空特征的细胞及神经环路机制，主要研究结果如下：1）选择性凋亡lPBN Oprm1+或Pdyn+神经元，或者从lPBN投射到下丘脑背内侧区(dorsal medial regions of hypothalamus，dmH) 的Oprm1+（lPBN^Oprm1→dmH）或Pdyn+（lPBN^Pdyn→dmH）神经元后，足底注射辣椒素引起的触诱发痛的时程显著延长（从几个小时到至少两周时间），同时，SNI模型引起的触诱发痛从单侧变成了双侧；2）采用化学遗传学的方法抑制lPBN Oprm1+或Pdyn+神经元，或者沉默投射到dmH的lPBN Oprm1+或Pdyn+神经元的轴突末梢，原本已经恢复的双侧触诱发痛复发；3）在对照实验中我们发现，沉默从lPBN投射至中央杏仁核（central amygdala, CeA）的Oprm1神经元的轴突末梢（lPBN^Oprm1→CeA）显著减弱了热痛，而对触诱发痛没有显著的影响；4）小鼠足底注射辣椒素后，投射至dmH的lPBN Oprm1神经元的兴奋性升高；5）在dvlPBN，Oprm1+神经元与Pdyn+神经元有部分共表达。为了进一步明确控制触诱发痛时空特征的投射神经元类型，我们在Oprm1^cre/+; Pdyn^Flpo/+的小鼠上，采用既依赖cre又依赖flpo的AAV定位注射到lPBN，从而在Oprm1+/Pdyn+的神经元上表达hM4Di受体以沉默此类神经元。研究结果表明，抑制投射到dmH的lPBN Oprm1+/Pdyn+神经元的轴突末梢，原本已经恢复的双侧触诱发痛复发，行为学结果与分别沉默投射到dmH的lPBN Oprm1+或Pdyn+神经元的轴突末梢相同。综上所述，我们的研究结果证明，从lPBN投射至dmH的Oprm1+和/或Pdyn+神经元在时间和空间上控制外周炎症和神经损伤引起的机械痛觉敏化。后续拟开展更多实验以确定lPBN Oprm1+还是Pdyn+神经元，或者是Oprm1+/Pdyn+神经元在触诱发痛的时空控制中起至关重要的作用。

本研究首次揭示了一条或两条从脑干外侧臂旁核直接投射到下丘脑背内侧区的阿片肽能神经通路（lPBN^Oprm1/Pdyn→dmH），该通路控制外周炎症或神经损伤引起的机械痛觉敏化的持续时间和敏化范围。本研究结果有望为临床上顽固性和难治性的异常触诱发痛的药物研发和临床治疗提供细胞和环路特异的靶点和新的思路。

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