Downregulation of metabotropic glutamate receptor 5 alleviates central sensitization by activating autophagy via inhibiting mTOR pathway in a rat model of chronic migraine

Abstract Background 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. Methods 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. Results 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. Conclusions 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.

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Metabotropic Glutamate Receptor 5 Regulates Synaptic Plasticity in a Chronic Migraine Rat Model Through the PKC/NR2B Signal

10.21203/rs.3.rs-84035/v1 ◽

2020 ◽

Author(s):

Yingying Niu ◽

Xiaoxu Zeng ◽

Lilin Zhao ◽

Yang Zhou ◽

Guangcheng Qin ◽

...

Keyword(s):

Synaptic Plasticity ◽

Chronic Migraine ◽

Glutamate Receptor ◽

Rat Model ◽

Central Sensitization ◽

Metabotropic Glutamate Receptor ◽

Adenosine Monophosphate ◽

Metabotropic Glutamate Receptor 5 ◽

Metabotropic Glutamate ◽

Synaptic Ultrastructure

Abstract Background: The mechanism of chronic migraine(CM) is complex, central sensitization is considered as one of the pathological mechanism. Synaptic plasticity is the basis of the 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. Methods: 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 blotting. 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) and synaptic ultrastructure were detected to explore synaptic plasticity. Results: We found that the expression of mGluR5 was upregulated in CM rats. Downregulated the mGluR5 with MPEP alleviated the allodynia and central sensitization. Moreover, mGluR5 regulated the synaptic plasticity by PKC/NR2B signal. Conclusions: These results indicate that mGluR5 contributed 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.

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