NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model.
NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model.
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NR2B-Tyr 磷酸化调节慢性偏头痛大鼠模型中枢敏化的突触可塑性
DOI：
10.1186/s10194-018-0935-2
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发表时间：
2018-11-06
期刊：
影响因子：
--
通讯作者：
Chen LX
中科院分区：
文献类型：
--
作者：
Wang XY;Zhou HR;Wang S;Liu CY;Qin GC;Fu QQ;Zhou JY;Chen LX
背景慢性偏头痛（CM）的发病机制尚不清楚，但可能与中枢敏感化和神经元持续性高兴奋有关。据报道，NR 2B的酪氨酸磷酸化（NR 2B-pTyr）有助于脊髓中中枢致敏和持续性疼痛的发展。中枢致敏被认为与突触效率的增加有关，但NR 2B-pTyr调节突触参与CM相关中枢致敏的机制尚不清楚。在这项研究中，我们的目的是探讨NR 2B-pTyr在调节突触可塑性的CM相关的中央sensitivity.MethodsMale Sprague-Dawley大鼠进行了7炎症汤（IS）注射模型反复三叉神经血管或硬脑膜伤害性感受器激活，这是假设发生在CM患者。采用vonFrey试验检测机械性退缩阈值的变化，采用免疫印迹法和免疫荧光染色法检测三叉神经尾侧核（TNC）中NR 2B-pTyr的表达。用Src家族激酶抑制剂4-氨基-5-（4-氯苯基）-7-（叔丁基）-吡唑并[3，4-d]嘧啶（PP 2）和蛋白酪氨酸激酶抑制剂genistein阻断NR 2B-pTyr，检测降钙素基因相关肽（CGRP）、P物质（SP）和突触蛋白突触后密度95（PSD 95）、突触素（Syp）、突触结合蛋白1（Syt-1）的变化。透射电镜观察突触超微结构，Golgi-Cox染色观察TNC神经元树突状结构。结果反复注射IS可诱导TNC神经元机械性异常痛，并显著增加TNC中NR 2B-Tyr-1472磷酸化（pNR 2B-Y1472）和NR 2B-Tyr-1252磷酸化（pNR 2B-Y1252）的表达。此外，PP 2和genistein抑制NR 2B-pTyr可减轻触诱发痛，降低CGRP、SP、PSD 95、Syp和Syt-1的表达及突触传递。NR 2B酪氨酸磷酸化的抑制通过调节中枢敏化中的突触可塑性对阈值功能障碍和偏头痛发作具有保护作用。
BackgroundAlthough the mechanism of chronic migraine (CM) is unclear, it might be related to central sensitization and neuronal persistent hyperexcitability. The tyrosine phosphorylation of NR2B (NR2B-pTyr) reportedly contributes to the development of central sensitization and persistent pain in the spinal cord. Central sensitization is thought to be associated with an increase in synaptic efficiency, but the mechanism through which NR2B-pTyr regulates synaptic participation in CM-related central sensitization is unknown. In this study, we aim to investigate the role of NR2B-pTyr in regulating synaptic plasticity in CM-related central sensitization.MethodsMale Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections to model recurrent trigeminovascular or dural nociceptor activation, which is assumed to occur in patients with CM. We used the von Frey test to detect changes in mechanical withdrawal thresholds, and western blotting and immunofluorescence staining assays were performed to detect the expression of NR2B-pTyr in the trigeminal nucleus caudalis (TNC). NR2B-pTyr was blocked with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)-pyrazolo [3,4-d] pyrimidine (PP2) and the protein tyrosine kinase inhibitor genistein to detected the changes in calcitonin gene-related peptide (CGRP), substance P (SP), and the synaptic proteins postsynaptic density 95 (PSD95), synaptophysin (Syp), synaptotagmin1 (Syt-1). The synaptic ultrastructures were observed by transmission electron microscopy (TEM), and the dendritic architecture of TNC neurons was observed by Golgi-Cox staining.ResultsStatistical analyses revealed that repeated infusions of IS induced mechanical allodynia and significantly increased the expression of NR2B Tyr-1472 phosphorylation (pNR2B-Y1472) and NR2B Tyr-1252 phosphorylation (pNR2B-Y1252) in the TNC. Furthermore, the inhibition of NR2B-pTyr by PP2 and genistein relieved allodynia and reduced the expression of CGRP, SP, PSD95, Syp and Syt-1 and synaptic transmission.ConclusionsThese data indicate that NR2B-pTyr might regulate synaptic plasticity in central sensitization in a CM rat model. The inhibition of NR2B tyrosine phosphorylation has a protective effect on threshold dysfunction and migraine attacks through the regulation of synaptic plasticity in central sensitization.
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影响因子：
3.5
作者：
Ji Y;Bai G;Cao DY;Traub RJ
通讯作者：
Traub RJ
DOI：
10.1073/pnas.0609307104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ehrlich, Ingrid;Klein, Matthew;Malinow, Roberto
通讯作者：
Malinow, Roberto
DOI：
10.1177/0333102415574845
发表时间：
2015-11
期刊：
Cephalalgia : an international journal of headache
影响因子：
--
作者：
Kunkler PE;Zhang L;Pellman JJ;Oxford GS;Hurley JH
通讯作者：
Hurley JH
DOI：
10.3233/ves-2012-0433
发表时间：
2011
期刊：
Journal of vestibular research : equilibrium & orientation
影响因子：
--
作者：
Burstein R;Jakubowski M;Rauch SD
通讯作者：
Rauch SD
弓状核中蛋白激酶 C 对 NR2B NMDA 亚基的磷酸化导致大鼠炎症性疼痛。
影响因子：
4.6
作者：
Bu F;Tian H;Gong S;Zhu Q;Xu GY;Tao J;Jiang X
通讯作者：
Jiang X