Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3expression and decreasing spinal microglial activation

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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IKBKB siRNA-Encapsulated Poly (Lactic-co-Glycolic Acid) Nanoparticles Diminish Neuropathic Pain by Inhibiting Microglial Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22115657 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5657

Author(s):

Seounghun Lee ◽

Hyo-Jung Shin ◽

Chan Noh ◽

Song-I Kim ◽

Young-Kwon Ko ◽

...

Keyword(s):

Neuropathic Pain ◽

Microglial Activation ◽

Glycolic Acid ◽

Nuclear Factor Kappa B ◽

Decisive Role ◽

Plga Nanoparticles ◽

Spinal Nerve ◽

Nuclear Factor ◽

Interfering Rna

Activation of nuclear factor-kappa B (NF-κB) in microglia plays a decisive role in the progress of neuropathic pain, and the inhibitor of kappa B (IκB) is a protein that blocks the activation of NF-κB and is degraded by the inhibitor of NF-κB kinase subunit beta (IKBKB). The role of IKBKB is to break down IκB, which blocks the activity of NF-kB. Therefore, it prevents the activity of NK-kB. This study investigated whether neuropathic pain can be reduced in spinal nerve ligation (SNL) rats by reducing the activity of microglia by delivering IKBKB small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles. PLGA nanoparticles, as a carrier for the delivery of IKBKB genes silencer, were used because they have shown potential to enhance microglial targeting. SNL rats were injected with IKBKB siRNA-encapsulated PLGA nanoparticles intrathecally for behavioral tests on pain response. IKBKB siRNA was delivered for suppressing the expression of IKBKB. In rats injected with IKBKB siRNA-encapsulated PLGA nanoparticles, allodynia caused by mechanical stimulation was reduced, and the secretion of pro-inflammatory mediators due to NF-κB was reduced. Delivering IKBKB siRNA through PLGA nanoparticles can effectively control the inflammatory response and is worth studying as a treatment for neuropathic pain.

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Electroacupuncture alleviates neuropathic pain by modulating Th2 infiltration and inhibiting microglial activation in the spinal cord of rats with spared nerve injury

World Journal of Traditional Chinese Medicine ◽

10.4103/wjtcm.wjtcm_40_20 ◽

2020 ◽

Vol 6 (4) ◽

pp. 448

Author(s):

Ru-Rong Wang ◽

Bin Liu ◽

Wei Long

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Nerve Injury ◽

Microglial Activation ◽

Spared Nerve Injury

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Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21072390 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2390

Author(s):

Masamichi Shinoda ◽

Satoshi Fujita ◽

Shiori Sugawara ◽

Sayaka Asano ◽

Ryo Koyama ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Electrical Stimulation ◽

Dorsal Horn ◽

Nerve Injury ◽

Spinal Cord Stimulation ◽

Microglial Activation ◽

In Vivo Optical Imaging ◽

Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

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Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Journal of Clinical Medicine ◽

10.3390/jcm8060890 ◽

2019 ◽

Vol 8 (6) ◽

pp. 890 ◽

Cited By ~ 12

Author(s):

Andrés Felipe Díaz ◽

Sara Polo ◽

Núria Gallardo ◽

Sergi Leánez ◽

Olga Pol

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Prefrontal Cortex ◽

Emotional Disorders ◽

Microglial Activation ◽

Antioxidant Properties ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Antidepressant Effects

Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain.

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N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury

Marine Drugs ◽

10.3390/md18100516 ◽

2020 ◽

Vol 18 (10) ◽

pp. 516 ◽

Cited By ~ 1

Author(s):

Anna A. Tyrtyshnaia ◽

Evgenia L. Egorova ◽

Anna A. Starinets ◽

Arina I. Ponomarenko ◽

Ekaterina V. Ermolenko ◽

...

Keyword(s):

Neuropathic Pain ◽

Microglial Activation ◽

Lipid Analysis ◽

Hippocampal Neurogenesis ◽

Raw Material ◽

Long Term Memory ◽

Inflammatory Factor ◽

Behavioral Experiments ◽

Chronic Neuropathic Pain ◽

The Brain

Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.

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Cathepsin S is increased in cerebrospinal fluid from patients with neuropathic pain—A support of the microglia hypothesis in humans

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2014.05.015 ◽

2014 ◽

Vol 5 (3) ◽

pp. 208-209

Author(s):

Torsten Gordh ◽

Anne-Li Lind ◽

Constantin Bodolea ◽

Ellen Hewitt ◽

Anders Larsson

Keyword(s):

Cerebrospinal Fluid ◽

Neuropathic Pain ◽

Microglial Activation ◽

Animal Experiments ◽

Cathepsin S ◽

Control Group ◽

Chronic Neuropathic Pain ◽

Potential Biomarker ◽

New Treatment ◽

Pain Patients

AbstractAimsCathepsin S has been reported to be a biomarker of spinal microglial activation, a process suggested to be involved in the pathophysiology of chronic neuropathic pain. So far this has been shown only in animal experiments. The aim of this study was to investigate the concentrations of cathepsin S in human cerebrospinal fluid (CSF) samples from a well-defined patient cohort suffering from neuropathic pain as compared to controls.MethodsCSF samples from patients suffering from chronic neuropathic pain (n = 14) were analyzed for cathepsin S levels using commercial sandwich ELISAs (DY1183, R&D Systems, Minneapolis, MN, USA). Control CSF was sampled from patients undergoing minor urological surgical procedures under spinal anaesthesia (n = 70), having no obvious pain suffering.ResultsThe neuropathic pain group had significantly higher levels of CSF cathepsin S (median 15189 pg/mL, range 3213–40,040), than the control group (median 5911 pg/mL, range 1909–17,188) (p < 0.005, Mann–Whitney U-test).ConclusionThe results support the existence of microglial activation in chronic neuropathic pain patients. CSF Cathepsin S may serve as a potential biomarker for this specific mechanism linked to neuropathic pain. In the future, Cathepsin S inhibiting drugs might become a new treatment alternative for neurophatic pain.

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Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat

Journal of Neuroimmunology ◽

10.1016/s0165-5728(97)00119-7 ◽

1997 ◽

Vol 79 (2) ◽

pp. 163-175 ◽

Cited By ~ 247

Author(s):

R.W Colburn ◽

J.A DeLeo ◽

A.J Rickman ◽

M.P Yeager ◽

P Kwon ◽

...

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Microglial Activation ◽

Pain Behaviors

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ATP mediates neuropathic pain in neuromyelitis optica via microglial activation

10.21203/rs.3.rs-107374/v1 ◽

2020 ◽

Author(s):

Teruyuki Ishikura ◽

Makoto Kinoshita ◽

Mikito Shimizu ◽

Yoshiaki Yasumizu ◽

Daisuke Motooka ◽

...

Keyword(s):

Neuropathic Pain ◽

Neuromyelitis Optica ◽

Transcriptome Analysis ◽

Mechanical Allodynia ◽

Microglial Activation ◽

Atp Release ◽

Common Symptom ◽

Pain Model ◽

Pharmacological Inhibition

Abstract Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. The aim of this study was to establish a novel animal model of NMOSD pain and to investigate its pathogenic mechanism. Methods We established an NMOSD pain model by injecting anti-AQP4 recombinant autoantibodies (AQP4-Ab) from NMOSD patient plasmablasts into rat spinal cords. We performed transcriptome analysis and pharmacological inhibition to elucidate the core mechanism of allodynia in the model. Results Development of mechanical allodynia was confirmed in the NMOSD pain model. AQP4-Ab mediated extracellular ATP release in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the NMOSD pain model. Furthermore, transcriptome analysis revealed microglial activation and elevated levels of IL-1β in NMOSD spinal cord. Inhibition of microglial activation and neutralization of IL-1β also attenuated neuropathic pain in the NMOSD rat model. In human patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. Conclusion A novel NMOSD pain model was established. ATP, microglial activation, and IL-1β secretion orchestrate the pathogenesis of NMOSD neuropathic pain.

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