Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

OnobotulintoxinA (OBT-A) is a treatment option for Chronic Migraine (CM). It works on central sensitization and pain but its mode of action is still unknown. To observe how OBT-A treatment works on single migraine attacks, this paper covers an over-6-month observation period through self-reported smartphone application data. This was an observational, open-label cohort study conducted on 34 CM patients under OBT-A treatment, selected between December 2016 and December 2017, who agreed to download a smartphone headache diary application (Aid Diary) according to the study instructions. The analysis was conducted using the smartphone application data reports on allodynia, intensity and extension of pain, and vegetative symptoms. We analysed a total of 707 records of single migraine attacks reported by compliant users (n = 34) in real-time. OBT-A significantly reduced allodynia, the number of vegetative symptoms, pain extension and intensity in single migraine attacks. Pain intensity was correlated with pain extension. In single migraine attacks, OBT-A improved symptoms of central sensitization. This action could be exerted by modulating nociceptive transmission and reducing the burden of single migraine episodes and improving the overall quality of life.

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NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model

The Journal of Headache and Pain ◽

10.1186/s10194-018-0935-2 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 18

Author(s):

Xue-Ying Wang ◽

Hui-Ru Zhou ◽

Sha Wang ◽

Chao-Yang Liu ◽

Guang-Cheng Qin ◽

...

Keyword(s):

Synaptic Plasticity ◽

Chronic Migraine ◽

Rat Model ◽

Central Sensitization

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Cerebrospinal Fluid Glutamate Levels in Chronic Migraine

Cephalalgia ◽

10.1111/j.1468-2982.2004.00750.x ◽

2004 ◽

Vol 24 (9) ◽

pp. 735-739 ◽

Cited By ~ 66

Author(s):

MFP Peres ◽

E Zukerman ◽

CA Senne Soares ◽

EO Alonso ◽

BFC Santos ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Chronic Migraine ◽

Glutamate Receptors ◽

Pain Score ◽

Clinical Data ◽

Central Sensitization ◽

Tender Points ◽

Data Link ◽

Headache Intensity ◽

Sensitization Process

Both preclinical and clinical data link glutamate to the migraine pathophisiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chornic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.

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P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

10.21203/rs.3.rs-67855/v1 ◽

2020 ◽

Author(s):

Li Jiang ◽

Yixin Zhang ◽

Feng Jing ◽

Ting Long ◽

Guangcheng Qin ◽

...

Keyword(s):

Chronic Migraine ◽

Central Sensitization ◽

Cellular Localization ◽

Microglial Activation ◽

Purinergic Receptor ◽

Radiant Heat ◽

Underlying Mechanism ◽

Autophagic Flux ◽

Pathophysiological Mechanism

Abstract Background: Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.Methods: The CM model was established by repeated intraperitoneal injection of nitroglycerin (NTG) in mice. A Von Frey filament and radiant heat were used to assess the mechanical and thermal hypersensitivity. Western blotting and immunofluorescence assays were performed to detect the expression of P2X7R, autophagy-related proteins, and the cellular localization of P2X7R. To determine the role of P2X7R and autophagy in CM, we detected the effects of the autophagy inducer, rapamycin (RAPA) and P2X7R antagonist, Brilliant Blue G (BBG), on pain behavior and the expression of calcitonin gene-related peptide (CGRP) and c-fos. In addition, the effect of RAPA and BBG on microglial activation and subsequent inflammation were investigated.Results: The expression of P2X7R was increased and was mainly colocalized with microglia in the TNC following recurrent NTG administration. The autophagic flux was blocked in CM, which was characterized by up-regulated LC3-II, and accumulated autophagy substrate protein, p62. RAPA significantly improved the basal rather than acute hyperalgesia. BBG alleviated both basal and acute hyperalgesia. BBG activated the level of autophagic flux. RAPA and BBG inhibited the activation of microglia, limited the inflammatory response, and reduced the expression of CGRP and c-fos. Conclusions: Our results demonstrate the dysfunction of the autophagic process in CM. Activated autophagy may have a preventive effect on migraine chronification. P2X7R contributes to central sensitization through mediating autophagy regulation and might become a potential target for CM.

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Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation

The Journal of Headache and Pain ◽

10.1186/s10194-021-01302-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Feng Jing ◽

Qian Zou ◽

Yangyang Wang ◽

Zhiyou Cai ◽

Yong Tang

Keyword(s):

Chronic Migraine ◽

Western Blotting ◽

Central Sensitization ◽

Microglial Activation ◽

Morphological Changes ◽

Trigeminal Nucleus ◽

Trigeminal Nucleus Caudalis ◽

Tnf Α

Abstract Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

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MicroRNA-155-5p promotes neuroinflammation and central sensitization via inhibiting SIRT1 in a nitroglycerin-induced chronic migraine mouse model

Journal of Neuroinflammation ◽

10.1186/s12974-021-02342-5 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Qianwen Wen ◽

Yunfeng Wang ◽

Qi Pan ◽

Ruimin Tian ◽

Dunke Zhang ◽

...

Keyword(s):

Mouse Model ◽

Chronic Migraine ◽

Central Sensitization ◽

Cellular Localization ◽

Microglial Activation ◽

Inflammatory Responses ◽

Neurological Diseases ◽

Thermal Hyperalgesia ◽

Qrt Pcr ◽

Tnf Α

Abstract Background Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM. Methods A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF. Results After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720. Conclusions These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice.

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Up‐regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine

Journal of Neurochemistry ◽

10.1111/jnc.14944 ◽

2020 ◽

Vol 155 (4) ◽

pp. 370-389 ◽

Cited By ~ 2

Author(s):

Xue Zhou ◽

Jie Liang ◽

Jiang Wang ◽

Zhaoyang Fei ◽

Guangcheng Qin ◽

...

Keyword(s):

Amino Acid ◽

Chronic Migraine ◽

Rat Model ◽

Central Sensitization ◽

Excitatory Amino Acid ◽

Amino Acid Transporter ◽

Excitatory Amino Acid Transporter ◽

Acid Transporter

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Repeated oxytocin prevents central sensitization by regulating synaptic plasticity via oxytocin receptor in a chronic migraine mouse model

The Journal of Headache and Pain ◽

10.1186/s10194-021-01299-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yunfeng Wang ◽

Qi Pan ◽

Ruimin Tian ◽

Qianwen Wen ◽

Guangcheng Qin ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Chronic Migraine ◽

Central Sensitization ◽

Antinociceptive Effect ◽

Adenosine Monophosphate ◽

Oxytocin Receptor ◽

Receptor Subtype ◽

Potential Candidate ◽

Associated Proteins

Abstract Background Central sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity. Methods A CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining. Results Our results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899. Conclusions Our findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.

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