scholarly journals Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Junlin Ouyang ◽  
Xiaping Chen ◽  
Shanchun Su ◽  
Xiaohui Li ◽  
Xueqin Xu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Viral Vectors ◽  
Synaptic Activity ◽  
Glutamatergic Neurons ◽  
Spinal Dorsal ◽  
Excitatory Neurons ◽  
Underlying Mechanisms

Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4–L6 spinal dorsal horn in Vglut2-cre+/– mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/– mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.

scholarly journals Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Riku Kawanabe ◽  
Kohei Yoshihara ◽  
Izuho Hatada ◽  
Makoto Tsuda
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Common Mechanism ◽  
Formalin Injection ◽  
Intraplantar Injection ◽  
Spinal Dorsal ◽  
Noxious Stimuli ◽  
Underlying Mechanisms

AbstractAstrocytes are critical regulators of neuronal function in the central nervous system (CNS). We have previously shown that astrocytes in the spinal dorsal horn (SDH) have increased intracellular Ca2+ levels following intraplantar injection of the noxious irritant, formalin. However, the underlying mechanisms remain unknown. We investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic) signaling because our recent study revealed the essential role of the astrocytic Ca2+ responses evoked by intraplantar capsaicin. Using in vivo SDH imaging, we found that the Ca2+ level increase in SDH astrocytes induced by intraplantar formalin injection was suppressed by ablation of SDH-projecting locus coeruleus (LC)-NAergic neurons. Furthermore, the formalin-induced Ca2+ response was dramatically decreased by the loss of α1A-adrenaline receptors (ARs) in astrocytes located in the superficial laminae of the SDH. Moreover, similar inhibition was observed in mice pretreated intrathecally with an α1A-AR-specific antagonist. Therefore, activation of α1A-ARs via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca2+ responses in the SDH evoked by noxious stimuli, including chemical irritants.

SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats

2020 ◽  
Vol 46 (1) ◽  
pp. 49-56
Author(s):  
Chenghua Zhou ◽  
Yufeng Zhang ◽  
Xiaowei Jiao ◽  
Guizhi Wang ◽  
Ruiyao Wang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Western Blot ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Manganese Superoxide Dismutase ◽  
Antioxidant Genes ◽  
Pain Hypersensitivity ◽  
Spinal Dorsal ◽  
Manganese Superoxide ◽  
Underlying Mechanisms

BackgroundThe underlying mechanisms of neuropathic pain remain unclear. This work aimed to investigate the role of Sirtuin3 (SIRT3), an nicotinamide adenosine dinucleotide+-dependent histone deacetylase, in the development of neuropathic pain induced by type 2 diabetes mellitus (T2DM) and to explore the associated mechanisms.MethodsDiabetic neuropathic pain (DNP) in rats was induced by high-fat diet/low-dose streptozotocin. The pain behaviors were examined using the von Frey and Hargreaves tests. The levels of SIRT3, manganese superoxide dismutase (MnSOD) and catalase (CAT) were determined using Western blot and RT-qPCR. The acetylation, phosphorylation and ubiquitination of forkhead box class O3a (FoxO3a) were analyzed by immunoprecipitation and Western blot.ResultsSIRT3 expression and activity were significantly reduced in the spinal dorsal horn of DNP model rats. Overexpression of spinal SIRT3 reversed the pain hypersensitivity in the DNP model rats, but knockdown of spinal SIRT3 mimicked the pain effect, eliciting pain hypersensitivity in normal rats. Moreover, overexpression of spinal SIRT3 in DNP model rats increased the FoxO3a level and upregulated the antioxidant genes MnSOD and CAT by deacetylating FoxO3a and inhibiting FoxO3a phosphorylation and ubiquitination. Knockdown of spinal SIRT3 in normal rats decreased the FoxO3a level and downregulated MnSOD and CAT by inhibiting the deacetylation of FoxO3a and further increasing FoxO3a phosphorylation and ubiquitination.ConclusionsThese results suggest that, by deacetylating FoxO3a and further reducing its phosphorylation, ubiquitination and degradation in the spinal dorsal horn, SIRT3 stabilizes FoxO3a protein and inhibits oxidative stress, resulting in pain alleviation in T2DM model rats.

scholarly journals A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior

2021 ◽  
Vol 118 (3) ◽  
pp. e2021220118
Author(s):  
Ryoichi Tashima ◽  
Keisuke Koga ◽  
Yu Yoshikawa ◽  
Misuzu Sekine ◽  
Moeka Watanabe ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Viral Vectors ◽  
Behavioral Responses ◽  
Lamina I ◽  
Spinal Dorsal ◽  
Low Threshold ◽  
Novel Strategy ◽  
Aβ Fibers

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP+) and show that specific ablation or silencing of AAV-NpyP+ SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP+ neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.

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.

Driving effect of BDNF in the spinal dorsal horn on neuropathic pain

2021 ◽  
pp. 135965
Author(s):  
Zhou Wu ◽  
Xie Zhiping ◽  
Li Chengcai ◽  
Zelong Xing ◽  
Xie Shenke ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Spinal Dorsal

353 INHIBITION OF COX-2 EXPRESSION IN RAT SPINAL DORSAL HORN BY ELECTROACUPUNCTURE IN NEUROPATHIC PAIN

2007 ◽  
Vol 11 (S1) ◽  
pp. S156-S157
Author(s):  
W.K. Lau ◽  
W.K. Chan ◽  
W.T. Chan ◽  
J.L. Zhang ◽  
H.Q. Zhang
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Spinal Dorsal ◽  
Cox 2

scholarly journals Hypersensitivity of Spinothalamic Tract Neurons Associated With Diabetic Neuropathic Pain in Rats

2002 ◽  
Vol 87 (6) ◽  
pp. 2726-2733 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Thermal Hyperalgesia ◽  
Diabetic Rats ◽  
Projection Neurons ◽  
Diabetic Neuropathic Pain ◽  
Spinothalamic Tract ◽  
Functional Changes ◽  
Spinal Dorsal

Diabetic neuropathic pain is often considered to be caused by peripheral neuropathy. The involvement of the CNS in this pathological condition has not been well documented. Development of hypersensitivity of spinal dorsal horn neurons is involved in neuropathic pain induced by traumatic nerve injury. In the present study, we determined the functional changes of identified spinothalamic tract (STT) neurons and their correlation to diabetic neuropathic pain. Diabetes was induced in rats by intraperitoneal injection of streptozotocin. Hyperalgesia and allodynia were assessed by the withdrawal responses to pressure, radiant heat, and von Frey filaments applied to the hindpaw. Single-unit activity of STT neurons was recorded from the lumbar spinal cord in anesthetized rats. The responses of STT neurons to mechanical and thermal stimuli and the sensitivity to intravenous morphine were determined in diabetic and normal rats. In 12 diabetic rats, mechanical allodynia and hyperalgesia, but not thermal hyperalgesia, developed within 2 wk after streptozotocin injection and lasted for ≥7 wk. Compared to the 32 STT neurons recorded in normal animals, the 37 STT neurons in diabetic rats displayed a higher spontaneous discharge activity and enlarged receptive fields. Also, the STT neurons in diabetic rats exhibited lower thresholds and augmented responses to mechanical stimulation. Intravenous injection of 2.5 mg/kg of morphine suppressed significantly the responses of STT neurons to noxious stimuli in 12 nondiabetic rats. However, such an inhibitory effect of morphine on the evoked response of STT neurons was diminished in 14 diabetic animals. This electrophysiological study provides new information that development of hypersensitivity of spinal dorsal horn projection neurons may be closely related to neuropathic pain symptoms caused by diabetes. Furthermore, the attenuated inhibitory effects of morphine on evoked responses of STT neurons in diabetes likely accounts for its reduced analgesic efficacy in this clinical form of neuropathic pain.

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