Astroglia in Medullary Dorsal Horn (Trigeminal Spinal Subnucleus Caudalis) Are Involved in Trigeminal Neuropathic Pain Mechanisms

Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of ‘patches’ of higher expression, interspersed within a less immunoreactive ‘matrix’, which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse areas of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.

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Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain

International Journal of Molecular Sciences ◽

10.3390/ijms22094564 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4564

Author(s):

Nuria García-Magro ◽

Yasmina B. Martin ◽

Pilar Negredo ◽

Francisco Zafra ◽

Carlos Avendaño

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Substantial Reduction ◽

Negative Control ◽

Infraorbital Nerve ◽

Survival Times ◽

Medullary Dorsal Horn ◽

Inhibitory Circuitry ◽

Basic Features ◽

Heterogeneous Reduction

Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of ‘patches’ of higher expression, interspersed within a less immunoreactive ‘matrix’, which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.

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Faculty Opinions recommendation of Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury.

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

10.3410/f.30481.486982 ◽

2006 ◽

Author(s):

Barry Sessle

Keyword(s):

Dorsal Horn ◽

Nerve Injury ◽

P38 Mapk ◽

Sensory Nerve ◽

Medullary Dorsal Horn

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Faculty Opinions recommendation of Treatment of central deafferentation and trigeminal neuropathic pain by motor cortex stimulation: report of a series of 20 patients.

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

10.3410/f.725993347.793558721 ◽

2019 ◽

Author(s):

Mark Obermann

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Motor Cortex Stimulation ◽

Trigeminal Neuropathic Pain

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Influence of intrathecal injection of p38 MAPK inhibitor on BDNF expression in dorsal horn of spinal cord of rats with neuropathic pain

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.00883 ◽

2010 ◽

Vol 30 (8) ◽

pp. 883-886

Author(s):

Xiao-di YAN ◽

Qian-bo CHEN ◽

Shuang-qiong ZHOU ◽

Hong-bin YUAN

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Dorsal Horn ◽

P38 Mapk ◽

Intrathecal Injection ◽

Bdnf Expression ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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Dorsal Horn Pain Mechanisms

The Oxford Handbook of the Neurobiology of Pain ◽

10.1093/oxfordhb/9780190860509.013.23 ◽

2019 ◽

pp. 444-469 ◽

Cited By ~ 1

Author(s):

Hanns Ulrich Zeilhofer ◽

Robert Ganley

Keyword(s):

Dorsal Horn ◽

Neuronal Excitability ◽

Functional Organization ◽

Synaptic Integration ◽

Synaptic Efficacy ◽

Pain Mechanisms ◽

Pain Pathway ◽

Pathological Pain ◽

The Subject ◽

Equivalent Structure

The spinal dorsal horn and its equivalent structure in the brainstem constitute the first sites of synaptic integration in the pain pathway. A huge body of literature exists on alterations in spinal nociceptive signal processing that contribute to the generation of exaggerated pain states and hence to what is generally known as “central sensitization.” Such mechanisms include changes in synaptic efficacy or neuronal excitability, which can be evoked by intense nociceptive stimulation or by inflammatory or neuropathic insults. Some of these changes cause alterations in the functional organization of dorsal horn sensory circuits, leading to abnormal pathological pain sensations. This article reviews the present state of this knowledge. It does not cover the contributions of astrocytes and microglia in detail as their functions are the subject of a separate chapter.

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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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