Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Stomatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
J Headache Pain. 2020 Dec 4;21(1):139. doi: 10.1186/s10194-020-01206-2.
The mechanism of chronic migraine (CM) is complex, central sensitization is considered as one of the pathological mechanism. Synaptic plasticity is the basis of central sensitization. Metabotropic glutamate receptor 5 (mGluR5) plays a vital role in the synaptic plasticity of the central nervous system. However, whether mGluR5 can promote the central sensitization by regulating synaptic plasticity in CM is unknown.
Male Wistar rats were used to establish a CM rat model, and the expression of mGluR5 mRNA and protein were detected by qRT-PCR and western blot. The allodynia was assessed by mechanical and thermal thresholds, and central sensitization was assessed by expression of the phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) at Serine 133(pCREB-S133) and c-Fos. The synaptic-associated protein postsynaptic density protein 95 (PSD), synaptophysin (Syp), and synaptophysin-1(Syt-1), synaptic ultrastructure, and dendritic spines were detected to explore synaptic plasticity. The expression of PKC, total NR2B(tNR2B), and phosphorylation of NR2B at Tyr1472(pNR2B-Y1472) were detected by western blot.
We found that the expression of mGluR5 was upregulated in CM rats. Downregulated the mGluR5 with MPEP alleviated the allodynia and reduced the expression of CGRP, pCREB-S133, c-Fos, PSD, Syp and Syt-1 and synaptic transmission. Moreover, the administration of MPEP inhibited the upregulation of PKC and pNR2B-Y1472.
These results indicate that mGluR5 contributes to central sensitization by regulating synaptic plasticity in CM through the PKC/NR2B signal, which suggests that mGluR5 may be a potential therapeutic candidate for CM.
慢性偏头痛（CM）的发病机制复杂，中枢敏化被认为是其中一种病理机制。突触可塑性是中枢敏化的基础。代谢型谷氨酸受体 5（mGluR5）在中枢神经系统的突触可塑性中发挥着重要作用。然而，mGluR5 是否可以通过调节 CM 中的突触可塑性来促进中枢敏化尚不清楚。
使用雄性 Wistar 大鼠建立 CM 大鼠模型，通过 qRT-PCR 和 Western blot 检测 mGluR5 mRNA 和蛋白的表达。通过机械和热阈值评估痛觉过敏，通过磷酸化环磷酸腺苷反应元件结合蛋白（CREB）在丝氨酸 133 位（pCREB-S133）和 c-Fos 的表达评估中枢敏化。检测突触相关蛋白突触后密度蛋白 95（PSD）、突触小泡蛋白（Syp）和突触小体相关蛋白-1（Syt-1）、突触超微结构和树突棘，以探索突触可塑性。通过 Western blot 检测蛋白激酶 C（PKC）、总 NR2B（tNR2B）和 NR2B 在酪氨酸 1472 位的磷酸化（pNR2B-Y1472）的表达。
我们发现 mGluR5 在 CM 大鼠中表达上调。用 MPEP 下调 mGluR5 可减轻痛觉过敏并降低 CGRP、pCREB-S133、c-Fos、PSD、Syp 和 Syt-1 的表达以及突触传递。此外，MPEP 的给药抑制了 PKC 和 pNR2B-Y1472 的上调。
这些结果表明，mGluR5 通过调节 PKC/NR2B 信号通路在 CM 中通过调节突触可塑性参与中枢敏化，这表明 mGluR5 可能是 CM 的潜在治疗靶点。
