Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury.
Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury.
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前扣带皮层的神经炎症：运动纤维损伤后镜像疼痛的潜在脊髓上机制
DOI：
10.1186/s12974-022-02525-8
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发表时间：
2022-06-20
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
周围神经炎症或损伤会影响对侧健康结构，进而导致镜像痛。脊髓以上结构在镜像痛的发生过程中发挥着重要作用。前扣带回皮质（ACC）是对疼痛刺激产生反应的一级皮质区域。在本研究中，我们利用单侧疼痛模型（ spared nerve injury，SNI， spared nerve injury即坐骨神经分支选择性损伤 ）和镜像痛模型（L5 腹根切断术，L5 - VRT），系统地研究并比较双侧ACC区域的神经免疫变化，旨在探究镜像痛潜在的脊髓以上神经免疫机制。
采用von Frey 纤维丝的上下法测量机械性异常性疼痛。通过注射用于设计药物特异性激活设计受体（DREADD）的病毒来调节ACC谷氨酸能神经元。运用免疫组织化学、免疫荧光、蛋白质免疫印迹、蛋白质微阵列技术检测炎症信号的调控情况。
在SNI组中，观察到单侧神经损伤诱导的ACC中肿瘤坏死因子-α（TNF - α）、白细胞介素 - 6（IL - 6）和趋化因子CX3CL1的表达增加出现在对侧，而在L5 - VRT组中则出现在双侧，这表明L5 - VRT手术引发了更强的免疫反应。在远距离的ACC中，SNI和L5 - VRT均诱导Nav1.6（SCN8A）蛋白水平在双侧显著增加，Nav1.6是一种主要的电压门控钠通道（VGSC），在哺乳动物神经系统中调节神经元活动。然而，L5 - VRT诱导的Nav1.6反应出现在术后3天，早于SNI诱导的反应（术后7天）。通过DREADD - Gq或DREADD - Gi调节ACC谷氨酸能神经元，极大地改变了ACC中CX3CL1水平和机械性缩爪阈值。对侧注射抗CX3CL1抗体中和内源性ACC CX3CL1，减弱了机械性异常性疼痛的诱导和维持，并消除了SNI诱导的ACC中CX3CL1、TNF - α和Nav1.6蛋白水平的上调。此外，对侧ACC注射抗CX3CL1抗体还抑制了同侧脊髓中c - Fos、Iba1、CD11b、TNF - α和IL - 6的表达。
由CX3CL1及其下游级联介导的下行易化功能可能起着关键作用，导致疼痛敏化增强，甚至引发镜像痛。针对趋化因子介导的ACC过度兴奋的策略，可能为神经性疼痛的治疗带来新的疗法。
在线版本包含补充材料，网址为10.1186/s12974 - 022 - 02525 - 8 。
Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus result in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first-order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC glutamatergic neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling. Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC glutamatergic neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain. The online version contains supplementary material available at 10.1186/s12974-022-02525-8.
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影响因子：
4.6
作者：
Ciccone, Roselia;Franco, Cristina;Pannaccione, Anna
通讯作者：
Pannaccione, Anna
DOI：
10.1093/brain/awaa208
发表时间：
2020-08-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Chen, Lubin;Huang, Jianying;Dib-Hajj, Sulayman D
通讯作者：
Dib-Hajj, Sulayman D
DOI：
10.1073/pnas.0610811104
发表时间：
2007-06-19
影响因子：
11.1
作者：
Clark, Anna K.;Yip, Ping K.;Malcangio, Marzia
通讯作者：
Malcangio, Marzia
背根神经节和脊髓中趋化因子 CXCL12 的上调有助于大鼠神经损伤后神经病理性疼痛的发生和维持
影响因子：
5.6
作者：
Bai, Liying;Wang, Xinru;Xu, Ji-Tian
通讯作者：
Xu, Ji-Tian
DOI：
10.1002/cne.22392
发表时间：
2010-08-15
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Davidson S;Truong H;Giesler GJ Jr
通讯作者：
Giesler GJ Jr