scholarly journals Transcription Repressor Hes1 Contributes to Neuropathic Pain Development by Modifying CDK9/RNAPII-Dependent Spinal mGluR5 Transcription

2019 ◽  
Vol 20 (17) ◽  
pp. 4177 ◽  
Author(s):  
Ming-Chun Hsieh ◽  
Hsien-Yu Peng ◽  
Yu-Cheng Ho ◽  
Cheng-Yuan Lai ◽  
Jen-Kun Cheng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Rna Polymerase Ii ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Cyclin Dependent Kinase ◽  
Metabotropic Glutamate ◽  
Interfering Rna ◽  
Transcription Expression

Diverse transcriptional controls in the dorsal horn have been observed in pain hypersensitivity. However, the understanding of the exact causes and mechanisms of neuropathic pain development is still fragmentary. Here, the results demonstrated nerve injury decreased the expression of spinal hairy and enhancer of split 1 (Hes1), a transcriptional repressor, and enhanced metabotropic glutamate receptor subtype 5 (mGluR5) transcription/expression, which was accompanied with behavioral allodynia. Moreover, nerve injury decreased Hes1 levels and reciprocally increased cyclin dependent kinase-9 (CDK9) levels and recruited CDK9 to phosphorylate RNA polymerase II (RNAPII) in the promoter fragments of mGluR5, thereby enhancing mGluR5 transcription/expression in the dorsal horn. These effects were also induced by intrathecally administering naïve rats with Hes1 small interfering RNA (siRNA). Conversely, Hes1 overexpression using intrathecal lentiviral vectors in nerve injury rats produced reversal of pain behavior and reversed protein expressions, phosphorylation, and coupling to the promoter segments in the dorsal horn. Collectively, the results in this study indicated nerve injury diminishes spinal Hes1-dependent suppression of CDK9-dependent RNAPII phosphorylation on the mGluR5 promoter that possibly enhances mGluR5 transcription/expression for neuropathic pain development.

The inhibiting role of periaqueductal gray metabotropic glutamate receptor subtype 8 in a rat model of central neuropathic pain

2020 ◽  
Vol 42 (6) ◽  
pp. 515-521 ◽  
Author(s):  
Marjan Hosseini ◽  
Mohsen Parviz ◽  
Alireza P. Shabanzadeh ◽  
Elham Zamani ◽  
Parvaneh Mohseni-Moghaddam ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Glutamate Receptor ◽  
Rat Model ◽  
Metabotropic Glutamate Receptor ◽  
Periaqueductal Gray ◽  
Receptor Subtype ◽  
Central Neuropathic Pain ◽  
Metabotropic Glutamate

The metabotropic glutamate receptor subtype mGluR 2/3 is located at extrasynaptic loci in rat spinal dorsal horn synapses

2000 ◽  
Vol 287 (3) ◽  
pp. 236-238 ◽  
Author(s):  
Jon Jatsu Azkue ◽  
José Marı́a Mateos ◽  
Izaskun Elezgarai ◽  
Rocı́o Benı́tez ◽  
Alexandra Osorio ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Glutamate Receptor ◽  
Spinal Dorsal Horn ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Spinal Dorsal

scholarly journals Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain

2020 ◽  
Vol 16 ◽  
pp. 174480692091533
Author(s):  
Sisi Chen ◽  
Feni Kadakia ◽  
Steve Davidson
Keyword(s):  
Neuropathic Pain ◽  
Anterior Cingulate Cortex ◽  
Glutamate Receptor ◽  
Inflammatory Pain ◽  
Metabotropic Glutamate Receptor ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Group Ii

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a GRM2Cre:tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex. GRM2encodes the group II metabotropic glutamate receptor subtype 2 which possesses analgesic properties in mouse and human models, although its function in the anterior cingulate cortex is not known. The majority of GRM2-tdtomato anterior cingulate cortex neurons expressed GRM2gene product in situ but did not overlap with cortical markers of local inhibitory interneurons, parvalbumin or somatostatin. Physiological properties of GRM2-tdtomato anterior cingulate cortex neurons were investigated using whole-cell patch clamp techniques in slice from animals with neuropathic or inflammatory pain, and controls. After hind-paw injection of Complete Freund’s Adjuvant or chronic constriction injury, GRM2-tdtomato anterior cingulate cortex neurons exhibited enhanced excitability as measured by an increase in the number of evoked action potentials and a decreased rheobase. This hyperexcitability was reversed pharmacologically by bath application of the metabotropic glutamate receptor subtype 2 agonist (2R, 4R)-4-Aminopyrrolidine-2,4-dicarboxylate APDC (1 µM) in both inflammatory and neuropathic models. We conclude that layer II/III pyramidal GRM2-tdtomato anterior cingulate cortex neurons express functional group II metabotropic glutamate receptors and undergo changes to membrane biophysical properties under conditions of inflammatory and neuropathic pain.

Role of Metabotropic Glutamate Receptor Subtype mGluR1 in Brief Nociception and Central Sensitization of Primate STT Cells

1999 ◽  
Vol 82 (1) ◽  
pp. 272-282 ◽  
Author(s):  
Volker Neugebauer ◽  
Ping-Sun Chen ◽  
William D. Willis
Keyword(s):  
Dorsal Horn ◽  
Central Sensitization ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Spinothalamic Tract ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs

G-protein coupled metabotropic glutamate receptors (mGluRs) are important modulators of synaptic transmission in the mammalian CNS and have been implicated in various forms of neuroplasticity and nervous system disorders. Increasing evidence also suggests an involvement of mGluRs in nociception and pain behavior although the contribution of individual mGluR subtypes is not yet clear. Subtypes mGluR1 and mGluR5 are classified as group I mGluRs and share the ability to stimulate phosphoinositide hydrolysis and activate protein kinase C. The present study examined the role of group I mGluRs in nociceptive processing and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 10 anesthetized male monkeys ( Macaca fascicularis) extracellular recordings were made from 20 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (BRUSH) and barely and substantially noxious (PRESS and PINCH, respectively) intensity were recorded before, during, and after the infusion of group I mGluR agonists and antagonists into the dorsal horn by microdialysis. Cumulative concentration–response relationships were obtained by applying different concentrations for at least 20 min each (at 5 μl/min). The actual concentrations reached in the tissue are 2–3 orders of magnitude lower than those in the microdialysis fibers (values in this paper refer to the latter). The group I antagonists were also applied at 10–25 min after capsaicin injection. S-DHPG, a group I agonist at both mGluR1 and mGluR5, potentiated the responses to innocuous and noxious stimuli (BRUSH > PRESS > PINCH) at low concentrations (10–100 μM; n = 5) but had inhibitory effects at higher concentrations (1–10 mM; n = 5). The mGluR5 agonist CHPG (1 μM-100 mM; n = 5) did not potentiate but inhibited all responses (10–100 mM; n = 5). AIDA (1 μM-100 mM), a mGluR1-selective antagonist, dose-dependently depressed the responses to PINCH and PRESS but not to BRUSH ( n = 6). The group I (mGluR1 > mGluR5) antagonist CPCCOEt (1 μM-100 mM) had similar effects ( n = 6). Intradermal injections of capsaicin sensitized the STT cells to cutaneous mechanical stimuli. The enhancement of the responses by capsaicin resembled the potentiation by the group I mGluR agonist S-DHPG (BRUSH > PRESS > PINCH). CPCCOEt (1 mM) reversed the capsaicin-induced sensitization when given as posttreatment ( n = 5). After washout of CPCCOEt, the sensitization resumed. Similarly, AIDA (1 mM; n = 7) reversed the capsaicin-induced sensitization and also blocked the potentiation by S-DHPG ( n = 5). These data suggest that the mGluR1 subtype is activated endogenously during brief high-intensity cutaneous stimuli (PRESS, PINCH) and is critically involved in capsaicin-induced central sensitization.

Alcohol Addiction- Metabotropic Glutamate Receptor Subtype 5 and its Ligands: How They All Come Together?

2018 ◽  
Vol 19 (8) ◽  
pp. 907-915 ◽  
Author(s):  
Jaya Kumar ◽  
Zalina Ismail ◽  
Nurul Hazwani Hatta ◽  
Najwa Baharuddin ◽  
Hermizi Hapidin ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Alcohol Addiction ◽  
Receptor Subtype ◽  
Metabotropic Glutamate

scholarly journals 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

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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