Neuron-glia signaling in trigeminal ganglion: Implications for migraine pathology
Neuron-glia signaling in trigeminal ganglion: Implications for migraine pathology
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DOI：
10.1111/j.1526-4610.2007.00854.x
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发表时间：
2007-07-01
期刊：
影响因子：
5
通讯作者：
Durham, Paul L.
中科院分区：
文献类型：
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作者：
Thalakoti, Srikanth;Patil, Vinit V.;Durham, Paul L.
目的：本研究的目的是利用三叉神经激活的体内模型，研究基础和炎症条件下三叉神经节内神经元-神经胶质细胞的信号转导。背景：三叉神经节神经的激活和降钙素基因相关肽(CGRP)的释放与偏头痛的病理有关。三叉神经细胞胞体位于神经节内，与神经胶质细胞关系密切。神经元-神经胶质细胞的相互作用涉及多种中枢神经系统(CNS)疾病引起的炎症和疼痛的所有阶段。然而，在正常和炎症条件下，三叉神经节内神经元-神经胶质细胞相互作用的作用尚不清楚。方法：利用SD大鼠研究三叉神经节神经元-神经胶质细胞信号转导。最初，True Blue被用作逆行示踪剂，通过荧光显微镜和多图像排列来定位神经节中的神经元胞体。染料偶联研究是在基础条件下进行的，并对辣椒素注射到TMJ胶囊中做出反应。化学刺激后用免疫组织化学方法检测S100B和p38在神经元和胶质细胞中的表达。用放射免疫法测定辣椒素对神经节内CGRP含量的影响。结果：在未受刺激的对照组动物中，真蓝主要分布在神经节内V3区(TMJ囊)、V2区(须垫)或V1区(眉毛和眼睛)内的神经细胞团中。然而，在注射辣椒素的动物获得的神经节V3区的神经元胞体和邻近的神经胶质细胞中都检测到了真蓝。注射辣椒素后，染料进入周围神经胶质细胞的时间与时间相关。化学刺激V3三叉神经可增加V3区神经元和胶质细胞炎症蛋白S100B和p38的表达。出乎意料的是，在神经节的V2和V1区域也观察到这些蛋白水平的增加。CGRP和囊泡停靠蛋白SNAP-25共同定位于许多神经元胞体和突起。刺激辣椒素后2小时，神经节内CGRP水平下降。蛋白质芯片分析表明，CGRP对培养的三叉神经节神经胶质细胞因子的分泌有不同的调节作用。结论：我们证实，三叉神经神经元的激活导致邻近神经胶质细胞的变化，这些变化涉及通过缝隙连接和旁分泌信号进行通讯。据我们所知，这是三叉神经节内神经元-神经胶质细胞通过缝隙连接发出信号的第一个证据。根据我们的发现，可能通过缝隙连接和旁分泌信号的神经元-神经胶质通讯参与了三叉神经节内外周敏化的发展，因此，可能在偏头痛的发生中发挥重要作用。此外，我们认为，炎症信号在神经节内的传播可能有助于解释通常报道的与偏头痛相关的共病症状。
Objective.-The goal of this study was to investigate neuronal-glial cell signaling in trigeminal ganglia under basal and inflammatory conditions using an in vivo model of trigeminal nerve activation.Background.-Activation of trigeminal ganglion nerves and release of calcitonin gene-related peptide (CGRP) are implicated in the pathology of migraine. Cell bodies of trigeminal neurons reside in the ganglion in close association with glial cells. Neuron-glia interactions are involved in all stages of inflammation and pain associated with several central nervous system (CNS) diseases. However, the role of neuron-glia interactions within the trigeminal ganglion under normal and inflammatory conditions is not known.Methods.-Sprague-Dawley rats were utilized to study neuron-glia signaling in the trigeminal ganglion. Initially, True Blue was used as a retrograde tracer to localize neuronal cell bodies in the ganglion by fluorescent microscopy and multiple image alignment. Dye-coupling studies were conducted under basal conditions and in response to capsaicin injection into the TMJ capsule. S100B and p38 expression in neurons and glia were determined by immunohistochemistry following chemical stimulation. CGRP levels in the ganglion were measured by radioimmunoassay in response to capsaicin. In addition, the effect of CGRP on the release of 19 different cytokines from cultured glial cells was investigated by protein microarray analysis.Results.-In unstimulated control animals, True Blue was detected primarily in neuronal cell bodies localized in clusters within the ganglion corresponding to the V3 region (TMJ capsule), V2 region (whisker pad), or V1 region (eyebrow and eye). However, True Blue was detected in both neuronal cell bodies and adjacent glia in the V3 region of the ganglion obtained from animals injected with capsaicin. Dye movement into the surrounding glia correlated with the time after capsaicin injection. Chemical stimulation of V3 trigeminal nerves was found to increase the expression of the inflammatory proteins S100B and p38 in both neurons and glia within the V3 region. Unexpectedly, increased levels of these proteins were also observed in the V2 and V1 regions of the ganglion. CGRP and the vesicle docking protein SNAP-25 were colocalized in many neuronal cell bodies and processes. Decreased CGRP levels in the ganglion were observed 2 hours following capsaicin stimulation. Using protein microarray analysis, CGRP was shown to differentially regulate cytokine secretion from cultured trigeminal ganglion glia.Conclusions.-We demonstrated that activation of trigeminal neurons leads to changes in adjacent glia that involve communication through gap junctions and paracrine signaling. This is the first evidence, to our knowledge, of neuron-glia signaling via gap junctions within the trigeminal ganglion. Based on our findings, it is likely that neuronal-glial communication via gap junctions and paracrine signaling are involved in the development of peripheral sensitization within the trigeminal ganglion and, thus, are likely to play an important role in the initiation of migraine. Furthermore, we propose that propagation of inflammatory signals within the ganglion may help to explain commonly reported symptoms of comorbid conditions associated with migraine.