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Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice

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Neural Regeneration Research 2023年第11期18卷 2545-2552页

作者： Fanning Zeng Jun Cao Zexuan Hong Yitian Lu Zaisheng Qin Tao Tao Department of Anesthesiology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Anesthesiology Central People’s Hospital of ZhanjiangZhanjiangGuangdong ProvinceChina Department of Anesthesiology Shenzhen Maternity&Child Healthcare HospitalSouthern Medical UniversityShenzhenGuangdong ProvinceChina

Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.

关键词： epigenetic m6A reader m6A MeRIP-Seq Nlrp1b neuropathic pain RNA methylation spared nerve injury Ythdf2

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Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following spared nerve injury in Rats

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Neuroscience Bulletin 2016年第1期32卷 27-40页

作者： Liying Bai Xinru Wang Zhisong Li Cunlong Kong Yonghui Zhao Jun-Liang Qian Quancheng Kan Wei Zhang Ji-Tian Xu Department of Physiology and Neurobiology Zhengzhou University School of Medicine Department of Anesthesiology The First Affiliated HospitalZhengzhou University Department of Pharmacy The First Affiliated HospitalZhengzhou University

Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.

关键词： spared nerve injury CXCL12 TNF-α Neuropathic pain Extracellular signal-regulated kinase Spinal cord

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Proteomic analysis of the dorsal spinal cord in the mouse model of spared nerve injury-induced neuropathic pain

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The Journal of Biomedical Research 2017年第6期31卷 494-502页

作者： Eun-sung Park Jung-mo Ahn Sang-min Jeon Hee-jung Cho Ki-myung Chung Je-yoel Cho Dong-ho Youn Department of Oral Physiology School of DentistryKyungpook National UniversityJung-guDaegu 41940R.O Korea Biocenter Incheon TechnoparkYeonsu-guIncheon 406-840R.O.Korea Department of Anatomy School of MedicineKyungpook National UniversityDong-in DongDaegu 700-422R.O Korea Department of Physiology and Neuroscience College of Dentistry and Research Institute of Oral ScienceGangneung-Wonju National UniversityGangneungGangwon-do 210-702R.O.Korea Department of Biochemistry College of Veterinary MedicineSeoul National UniversitySeoul 151-742R.O.Korea

Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to simultaneously analyze hundreds or thousands of proteins differentially expressed in the dorsal horn of the spinal cord in rats or dorsal root ganglion of rats with certain type of peripheral nerve injury. However, a proteomic study using a mouse model of neuropathic pain could be attempted because of abundant protein database and the availability of transgenic mice. In this study, whole proteins were extracted from the ipsilateral dorsal half of the 4th-6th lumbar spinal cord in a mouse model of spared nerve injury（SNI）-induced neuropathic pain. In-gel digests of the proteins size-separated on a polyacrylamide gel were subjected to reverse-phase liquid-chromatography coupled with electrospray ionization ion trap tandem mass spectrometry（MS/MS）. After identifying proteins, the data were analyzed with subtractive proteomics using ProtAn, an in-house analytic program. Consequently, 15 downregulated and 35 upregulated proteins were identified in SNI mice. The identified proteins may contribute to the maintenance of neuropathic pain,and may provide new or valuable information in the discovery of new therapeutic targets for neuropathic pain.

关键词： proteomics spinal dorsal horn neuropathic pain spared nerve injury mouse

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TNF-а-mediated upregulation of chemokine CXCL12 in dorsal root ganglia and spinal cord con-tributes to the development and maintenance of neuropathic pain following spared nerve injury in rats

TNF-а-mediated upregulation of chemokine CXCL12 in dorsal r...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：柏莉莹钱俊良张卫许继田郑州大学第一附属医院麻醉科郑州大学基础医学院生理学教研室

Emerging evidence indicates that CXCL12/CXCR4 signaling involves in chronic pain.But,little study has systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism.In this study we found that spared nerve injury（SNI）resulted in an increased expression of CXCL12 and its cognate receptor CXCR4 in L5 DRG neurons and satellite glial cells.SNI also aroused a long-lasting upregulation of CXCL12 and CXCR4 in ipsilateral L4-5 spinal cord dorsal horn,which characterized by CXCL12 expressed in neurons and CXCR4 colocalized with neurons and astrocytes.Meanwhile,SNI induced sustained increased expression of TNF-αin DRG and spinal cord.Intraperitoneal injection（i.p.）of TNF-α-synthesis inhibitor thalidomide,reduced the SNI-induced mechanical hypersensitivity,and inhibited the expression of CXCL12 in DRG and spinal cord.Intrathecal injection（i.t.）of CXCR4 antagonist AMD3100,began on 30 min before or 7 days after SNI,both resulted in reduction of behavioral signs of allodynia.Rats treated by a bolus i.***.or i.p.AMD3100 on 8th day of SNI attenuated abnormal pain behavior.The established neuropathic pain following SNI was also impaired by CXCL12 neutralizing antibody i.t..Moreover,repetitive AMD3100 i.***.prevented the activation of ERK in spinal cord.The CXCL12 i.t.-induced mechanical hypersensitivity in nave rats was alleviated by pretreatment with MEK inhibitor PD98059.Collectively,our results revealed that TNF-αmediated the upregulation of CXCL12 in DRG and spinal cord following SNI,and the CXCL12/CXCR4 signailing via ERK activation contributed to the development and maintenance of neuropathic pain.

关键词： spared nerve injury CXCL12 TNF-α Neuropathic pain Extracellular signal-regulated kinase

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Evaluation of NR2B peptide as subunit vaccines against experimental neuropathic pain

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Chinese Medical Journal 2007年第8期120卷 643-647页

作者： WANG Gong-ruing TIAN Yu-ke CHEN Jian-ping TIAN Xu-bi GAO Feng YANG Hui AN Ke MA Guo-ping Department of Anaesthesiology Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Background NR2B containing N-methyI-D-aspartate （NMDA） receptor plays an important role in the facilitation and maintenance of neuropathic pain. The discrete distribution of NR2B subunit in the central nervous system （CNS） may support reduced side effects of agents that act selectively at this site. Therefore, we investigated the hypothesis that a humoral autoimmune response targeting the NR2B subunit of NMDA receptor relieves pain like behaviours produced by peripheral injury. Methods Rats were immunized subcutaneously with NR2B-Keyhole Limpet Hemocyanin （NR2B-KLH） three times at two-week intervals. NR2B specific IgG titres in sera and cerebrospinal fluid were determined by indirect ELISA. Seven days after the third immunization, 2 of the 3 terminal branches of the sciatic nerve （tibial and common peroneal nerves） were tightly ligated. Behavioural testing was carried out on every other day after surgery, until 7 days after surgery. The lumbar spinal cord （L4-6） was removed on day 7 after ligation. The expression of NR2B protein in the lumbar spinal cord was determined using Western blotting. Results After the second vaccination, NR2B specific IgG in sera was detected to be 〉0.5 μg/ml in six of nine rats. After the third vaccination, all the immunized rats had 〉2.2 μg/ml. Titres of NR2B specific IgG in sera peaked 42 days post initial immunization and persisted for over 70 days. No NR2B specific IgG was detected in sera from PBS or KLH group. The behavioural thresholds in NR2B group were significantly higher than those in PBS and KLH groups on day 7 after ligation. NR2B specific IgG in CSF in NR2B group could not be detected on day 1 before spinal dissection; but could be detected on day 7 after surgery. The expression of NR2B protein in group NR2B was significantly lower than in PBS and KLH groups on day 7 after surgery. Conclusion The NR2B peptide could be used as a vaccine against neuropathic pain, which could be associated with reduction of NR2B protein in the lumbar spinal cord.

关键词： peripheral neuropathic pain immunization NR2B peptide vaccine spared nerve injury

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Intervertebral foramen injection of ozone relieves mechanical allodynia and enhances analgesic effect of gabapentin in animal model of neuropathic pain: A proof-of-concept study

Intervertebral foramen injection of ozone relieves mechanica...

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中国神经科学学会第十二届全国学术会议

作者： Wen-Jun Luo Fan Yang Fei Yang Wei Sun Wei Zheng Xiao-Liang Wang Fang-Fang Wu Jiang-Lin Wang Jia-Shuang Wang Su-Min Guan Jun Chen Institute for Biomedical Sciences of Pain Tangdu Hospital The Fourth Military Medical University Key Laboratory of Brain Stress and Behavior People’s Liberation Army Department of Pain Medicine Tianjin First Central Hospital Department of Pain Medicine Red-Cross Hospital Jinan University School of Stomatology The Fourth Military Medical University Beijing Institute for Brain Disorders

Objective In a clinical study, intervertebral foramen（I.V.F.） injection of ozone at the involved segmental levels could not only significantly alleviate paroxysmal spontaneous pain and mechanical allodynia, but also improve the quality of life in patients with chronic, intractable postherpetic neuralgia（PHN）. However, so far no basic research with animals has been available. The present study is to explore whether I.V.F. ozone has analgesia effect on animal models of neuropathic and inflammatory pain. Methods By I.V.F. injection, a volume of 50 μl ozone-oxygen mixture or air was carried out on male Sprague-Dawley rats of na?ve, inflammatory pain states produced by injections of either bee venom or complete Freud’s adjuvant, and neuropathic pain state produced by spared nerve injury（SNI）, respectively. Then the effect of combinational use of gabapentin（100 mg/1 kg body weight） with I.V.F. ozone was evaluated in SNI rats by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another four drugs, AMD3100（a CXCR4 antagonist）, A-803467（a selective Nav1.8 blocker）, rapamycin（the m TOR inhibitor）, and MGCD0103（a selective histone deacetylase inhibitor） were evaluated for long term enough through I.V.F. injection, respectively. Results（1） I.V.F. injection of ozone at L4-5 can selectively relieve mechanical allodynia in rats with neuropathic pain;（2） The analgesic effects of I.V.F. ozone lasted much longer（＞ 14 days） than other selective molecular target drugs（＜48 hours）;（3） Combinational use of systemic gabapentin and I.V.F. ozone produced synergistic analgesic effect in rats with neuropathic pain. Conclusion I.V.F. injection of ozone selectively relieved neuropathic pain but not inflammatory pain, and enhanced analgesic effect of gabapentin.

关键词： Chronic pain neuropathic pain inflammatory pain ozone therapy interventional therapy gabapentin spared nerve injury bee venom complete Freud’s adjuvant

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Red nucleus IL-6 participates in the maintenance of neuropathic pain through STAT3 and ERK signaling pathways

Red nucleus IL-6 participates in the maintenance of neuropat...

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中国神经科学学会第十二届全国学术会议

作者： Cui-Ping DING Yi-Jie GUO Hao-Nan LI Shui-Ping HAN Xiao-Yan ZENG Jun-Yang WANG Department of Pathogenic Biology and Immunology Xi'an Jiaotong University Health Science Center Department of Pathology Xi'an Jiaotong University Health Science Center Department of Laboratory Medicine The First Affiliated Hospital of Xi'an Jiaotong University

Objective The red nucleus（RN） is an important nucleus of extrapyramidal tract, serving as a critical subcortical relay station for a massive descending motor tract（the rubrospinal tract）. Apart from the well-established roles in the motor system, recent studies suggest that the RN is also involved in pain processing and aversive events. Our previous study has demonstrated that interleukin-6（IL-6） is up-regulated in the RN after spared nerve injury（SNI） and plays a facilitated role in the maintenance of neuropathic pain. However, the downstream signaling pathways of the RN IL-6 inducing abnormal pain are still unknown. Here, the roles of different signaling pathways, including signal transducer and activator of transcription 3（STAT3）, extracellular signal-regulated kinase（ERK）, c-Jun N-terminal kinase（JNK）, p38 mitogen-activated protein kinase（p38 MAPK） and Protein Kinase B（PKB）, in the RN IL-6-evoked mechanical allodynia were investigated. Methods The right tibial nerve and common peroneal nerve of rats were tight-ligated to built SNI neuropathic pain model. A single injection of recombinant rat IL-6（20 ng） into the left RN of normal rats was used to establish IL-6-evoked hypersensitivity model. The mechanical paw withdrawal thresholds（PWT） of the right hindpaw of rats were dynamically assessed using von Frey filaments. The expression levels of p-STAT3, p-ERK, p-JNK, p-p38 MAPK, p-PKB in the RN of rats were observed using immunohistochemistry and western blotting. To further study the roles of different downstream signaling pathways in IL-6-evoked mechanical allodynia, inhibitors against different signaling pathways [STAT3 inhibitor AG490（5.0 μg）, ERK inhibitor PD98059（2.5 μg）, JNK inhibitor SP600125（2.5 μg）, p38 MAPK inhibitor SB203580（10 μg） and p-PKB inhibitor LY294002（2.5 μg）] were respectively microinjected into the RN of rats with mechanical allodynia and the PWT changes of contralateral hindpaw were dynamically assessed. Results（1） Immunohistochemistry and western blotting demonstrated that significant up-

关键词： Red nucleus interleukin-6 neuropathic pain spared nerve injury

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D2- like but not D1- like dopamine receptors in ventrolateral orbital cortex are involved in apomorphine-induced antiallodynia in a neuropathic pain model of rats

D2- like but not D1- like dopamine receptors in ventrolatera...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Yong-Hui DANG~1,Yan ZHAO~1,Bo XING~1,Xiao-Jie ZHAO~1,Teng CHEN~1,Jing-Shi TANG~2,Fu-Quan HUO~2,Feng-Yi XU~2, Chao-LingQU~(2,*) 1 Department of Forensic Medicine,Key Laboratory of Environment and Gene Related to Diseases,Ministry of Education, Xi''an Jiaotong University School of Medicine,Xi''an 710061,China 2 Department of Physiology and Pathophysiology,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education,Xi''an Jiaotong University School of Medicine,Xi''an 710061,China

＜正＞Objective The ventrolateral orbital cortex（VLO） is part of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius（Sm） and a descending pathway to the spinal cord relaying in the periaqueductal gray（PAG）.The aim of the present study was to examine whether dopamine and its receptors are involved in the antinociception in VLO.Methods The animal model of persistent peripheral neuropathic pain-spared nerve injury（SNI） was used.The withdrawal threshold in response to von-Frey hair stimulation of the injury side hindpaw was measured as an index of mechanical allodynia.Results（1） Microinjection of the nonselective dopamine receptor agonist apomorphine（1.0,2.5,5.0μg in 0.5μl） into the VLO significantly increased the paw withdrawal threshold in a dose-dependent manner,which was reversed by pretreatment with selective D2-like dopamine receptor antagonist raclopride（1.5μg in 0.5μl）,but not selective D1-like dopamine receptor antagonist（SCH23390 5.0μg in 0.5μl）.（2） Microinjection of raclopride or SCH23390 alone into the VLO had no effects on mechanical paw withdrawal threshold. Conclusion The results suggest that dopamine neurotransmitter is involved in VLO-induced anti-allodynia,and this effect is mediated by D2-like but not Dl-like dopamine receptors.

关键词： ventrolateral orbital cortex dopamine receptor raclopride SCH23390 mechanical allodynia spared nerve injury rat

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