Spinophilin modulates pain through suppressing dendritic spine morphogenesis via negative control of Rac1-ERK signaling in rat spinal dorsal horn

Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

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Inhibition by dexmedetomidine of the activation of spinal dorsal horn glias and the intracellular ERK signaling pathway induced by nerve injury

Brain Research ◽

10.1016/j.brainres.2011.08.019 ◽

2012 ◽

Vol 1427 ◽

pp. 1-9 ◽

Cited By ~ 28

Author(s):

Ling Liu ◽

Fengtao Ji ◽

Jianjun Liang ◽

Huiyan He ◽

Yanni Fu ◽

...

Keyword(s):

Signaling Pathway ◽

Dorsal Horn ◽

Nerve Injury ◽

Spinal Dorsal Horn ◽

Erk Signaling ◽

Spinal Dorsal

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mGluR5/ERK signaling regulated the phosphorylation and function of glycine receptor α1ins subunit in spinal dorsal horn of mice

PLoS Biology ◽

10.1371/journal.pbio.3000371 ◽

2019 ◽

Vol 17 (8) ◽

pp. e3000371 ◽

Cited By ~ 2

Author(s):

Zi-Yang Zhang ◽

Hu-Hu Bai ◽

Zhen Guo ◽

Hu-Ling Li ◽

Yong-Tao He ◽

...

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Glycine Receptor ◽

Erk Signaling ◽

Spinal Dorsal ◽

And Function

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Single Intraperitoneal Injection of Low-Dose Ketamine Pretreatment Alleviates Mechanical Hyperalgesia and Downregulates the Expression of Inflammatory Cytokines in Spinal Dorsal Horn of Rats

Journal of Anesthesia and Perioperative Medicine ◽

10.24015/japm.2015.0032 ◽

2015 ◽

Vol 2 (5) ◽

pp. 236-243

Author(s):

Li Xu ◽

Yu Shen ◽

Lin Liu ◽

Yin Cui ◽

Xiao-Ping Gu ◽

...

Keyword(s):

Dorsal Horn ◽

Inflammatory Cytokines ◽

Intraperitoneal Injection ◽

Spinal Dorsal Horn ◽

Low Dose ◽

Mechanical Hyperalgesia ◽

Spinal Dorsal ◽

Single Intraperitoneal Injection

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Faculty Opinions recommendation of Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1105023.561186 ◽

2008 ◽

Author(s):

Nanna Finnerup

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Spinal Dorsal ◽

Spread Of Excitation

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Faculty Opinions recommendation of Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120062.576194 ◽

2008 ◽

Author(s):

Nanna Finnerup

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Spinal Dorsal ◽

Afferent Fibers

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Calcitonin gene-related peptide regulates spinal microglial activation through the histone H3 lysine 27 trimethylation via enhancer of zeste homolog-2 in rats with neuropathic pain

Journal of Neuroinflammation ◽

10.1186/s12974-021-02168-1 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Qi An ◽

Chenyan Sun ◽

Ruidi Li ◽

Shuhui Chen ◽

Xinpei Gu ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Nerve Injury ◽

Spinal Dorsal Horn ◽

Microglial Activation ◽

Microglial Cells ◽

Gene Promoters ◽

Spinal Dorsal ◽

Related Peptide ◽

Calcitonin Gene

Abstract Background Calcitonin gene-related peptide (CGRP) as a mediator of microglial activation at the transcriptional level may facilitate nociceptive signaling. Trimethylation of H3 lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) is an epigenetic mark that regulates inflammatory-related gene expression after peripheral nerve injury. In this study, we explored the relationship between CGRP and H3K27me3 in microglial activation after nerve injury, and elucidated the underlying mechanisms in the pathogenesis of chronic neuropathic pain. Methods Microglial cells (BV2) were treated with CGRP and differentially enrichments of H3K27me3 on gene promoters were examined using ChIP-seq. A chronic constriction injury (CCI) rat model was used to evaluate the role of CGRP on microglial activation and EZH2/H3K27me3 signaling in CCI-induced neuropathic pain. Results Overexpressions of EZH2 and H3K27me3 were confirmed in spinal microglia of CCI rats by immunofluorescence. CGRP treatment induced the increased of H3K27me3 expression in the spinal dorsal horn and cultured microglial cells (BV2) through EZH2. ChIP-seq data indicated that CGRP significantly altered H3K27me3 enrichments on gene promoters in microglia following CGRP treatment, including 173 gaining H3K27me3 and 75 losing this mark, which mostly enriched in regulation of cell growth, phagosome, and inflammation. qRT-PCR verified expressions of representative candidate genes (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) and real-time cell analysis (RTCA) verified microglial proliferation. Additionally, CGRP treatment and CCI increased expressions of ITGAM, ADAM10, MCP-1, and CX3CR1, key mediators of microglial activation in spinal dorsal horn and cultured microglial cells. Such increased effects induced by CCI were suppressed by CGRP antagonist and EZH2 inhibitor, which were concurrently associated with the attenuated mechanical and thermal hyperalgesia in CCI rats. Conclusion Our findings highly indicate that CGRP is implicated in the genesis of neuropathic pain through regulating microglial activation via EZH2-mediated H3K27me3 in the spinal dorsal horn.

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