Tactile allodynia can occur in the spared nerve injury model in the rat without selective loss of GABA or GABAA receptors from synapses in laminae I–II of the ipsilateral spinal dorsal horn

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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Spinal Dorsal Horn Calcium Channel 2 -1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Journal of Neuroscience ◽

10.1523/jneurosci.2982-04.2004 ◽

2004 ◽

Vol 24 (39) ◽

pp. 8494-8499 ◽

Cited By ~ 154

Author(s):

C.-Y. Li

Keyword(s):

Peripheral Nerve ◽

Calcium Channel ◽

Dorsal Horn ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Spinal Dorsal Horn ◽

Tactile Allodynia ◽

Spinal Dorsal

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Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model

Journal of Neuroinflammation ◽

10.1186/s12974-020-01991-2 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Yaping Wang ◽

Yu Shi ◽

Yongquan Huang ◽

Wei Liu ◽

Guiyuan Cai ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Response ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Intrathecal Administration ◽

Spared Nerve Injury ◽

Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. Results The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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158 COLD SENSITIVITY IS INCREASED IN SPINAL DORSAL HORN WIDE DYNAMIC RANGE (WDR) NEURONS IN SPARED NERVE INJURY (SNI) RATS

European Journal of Pain ◽

10.1016/j.ejpain.2007.03.173 ◽

2007 ◽

Vol 11 (S1) ◽

pp. S68-S69

Author(s):

L. Luo ◽

H. Gustafsson ◽

K. Hygge Blakeman ◽

K. Angeby-Moller ◽

O.-G. Berge

Keyword(s):

Dorsal Horn ◽

Nerve Injury ◽

Spinal Dorsal Horn ◽

Dynamic Range ◽

Cold Sensitivity ◽

Spared Nerve Injury ◽

Wide Dynamic Range ◽

Spinal Dorsal ◽

Wdr Neurons

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Expression and phosphorylation of ERM family proteins in rat spinal dorsal horn with spared nerve injury (SNI) model

Neuroscience Research ◽

10.1016/j.neures.2009.09.1192 ◽

2009 ◽

Vol 65 ◽

pp. S215

Author(s):

Ryosuke Kashimoto ◽

Hiroki Yamanaka ◽

Kimiko Kobayashi ◽

Masamichi Okubo ◽

Osamu Mimura ◽

...

Keyword(s):

Dorsal Horn ◽

Nerve Injury ◽

Spinal Dorsal Horn ◽

Spared Nerve Injury ◽

Spinal Dorsal

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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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