NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model

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

Neuroscience Letters ◽

10.1016/j.neulet.2020.135552 ◽

2021 ◽

Vol 743 ◽

pp. 135552

Author(s):

Yingying Niu ◽

Xiaoxu Zeng ◽

Guangcheng Qin ◽

Dunke Zhang ◽

Jiying Zhou ◽

...

Keyword(s):

Chronic Migraine ◽

Glutamate Receptor ◽

Rat Model ◽

Central Sensitization ◽

Metabotropic Glutamate Receptor ◽

Mtor Pathway ◽

Metabotropic Glutamate Receptor 5 ◽

Metabotropic Glutamate

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Up‐regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine

Journal of Neurochemistry ◽

10.1111/jnc.14944 ◽

2020 ◽

Vol 155 (4) ◽

pp. 370-389 ◽

Cited By ~ 2

Author(s):

Xue Zhou ◽

Jie Liang ◽

Jiang Wang ◽

Zhaoyang Fei ◽

Guangcheng Qin ◽

...

Keyword(s):

Amino Acid ◽

Chronic Migraine ◽

Rat Model ◽

Central Sensitization ◽

Excitatory Amino Acid ◽

Amino Acid Transporter ◽

Excitatory Amino Acid Transporter ◽

Acid Transporter

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Repeated oxytocin prevents central sensitization by regulating synaptic plasticity via oxytocin receptor in a chronic migraine mouse model

The Journal of Headache and Pain ◽

10.1186/s10194-021-01299-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yunfeng Wang ◽

Qi Pan ◽

Ruimin Tian ◽

Qianwen Wen ◽

Guangcheng Qin ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Chronic Migraine ◽

Central Sensitization ◽

Antinociceptive Effect ◽

Adenosine Monophosphate ◽

Oxytocin Receptor ◽

Receptor Subtype ◽

Potential Candidate ◽

Associated Proteins

Abstract Background Central sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity. Methods A CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining. Results Our results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899. Conclusions Our findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.

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