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The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2018

Open Access 01-12-2018 | Research article

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

Authors: Xue-Ying Wang, Hui-Ru Zhou, Sha Wang, Chao-Yang Liu, Guang-Cheng Qin, Qing-Qing Fu, Ji-Ying Zhou, Li-Xue Chen

Published in: The Journal of Headache and Pain | Issue 1/2018

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Abstract

Background

Although 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.

Methods

Male 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.

Results

Statistical 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.

Conclusions

These 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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Metadata
Title
NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model
Authors
Xue-Ying Wang
Hui-Ru Zhou
Sha Wang
Chao-Yang Liu
Guang-Cheng Qin
Qing-Qing Fu
Ji-Ying Zhou
Li-Xue Chen
Publication date
01-12-2018
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2018
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-018-0935-2

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