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Formalin-induced astrocyte glutamate-glutamine cycle involved in rat spinal cord central sensitization

Neural Regeneration Research 2009年第11期4卷 918-922页

作者： Haili Shen Yufeng XieO Hua Han Yayi Xia Youcheng Zhang Cuifang Wang Jing Wang Institute of Orthopaedics Second Hospital of Lanzhou University Lanzhou 730030 Gansu Province China Robarts Research Institute University of Western Ontario 100 Perth Drive London ON Canada N6A 5K8 Department of General Surgery Second Hospital of Lanzhou University Lanzhou 730030 Gansu Province China

BACKGROUND： central sensitization, a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation, is an important mechanism underlying hyperalgesia and neuropathic pain. Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood. OBJECTIVE： To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Orthopedics, Second Hospital, Lanzhou University, China from September 2007 to August 2008. MATERIALS： Methionine sulfoximine （MSO, 0.1 mmol/L）, glutamine （0.25 mmol/L）, and formalin were used for this study. METHODS： A total of 43 male, Sprague Dawley rats, aged 4 months, were randomly assigned to a sham operation group （n = 6） and a model group （n = 37）. Rats in the model group received intrathecal infusion in the spinal cord. 7 days later, 37 model rats were randomly divided into PBS, MSO, glutamine, MSO ＋ glutamine and formalin subcutaneous injection alone groups. The PBS, MSO, glutamine, MSO ＋ glutamine groups were respectively intrathecally injected with PBS, MSO, glutamine, MSO ＋ glutamine （50 μL each）, and then infused with 10 μL of saline. Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord. At 15 minutes after intrathecal injection, a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5% formalin （50 μL） in the left hindpaw. MAIN OUTCOME MEASURES： Changes in spontaneous nociceptive behavior （licking/biting or flinching） were observed following formalin injection into the rat hindpaw. RESULTS： Compared with the PBS group, duration of licking/biting was significantly shortened, and flinching frequency was significantly diminished in the MSO group （P 〈 0.05）. Com

关键词： astrocyte glutamate-glutamine cycle central sensitization inflammatory pain spinal cord

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Correlation between self-reported recovery and central sensitization in whiplash patients

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Journal of Sport and Health Science 2012年第1期1卷 61-64页

作者： Robert Ferrari Department of Medicine University of AlbertaEdmontonAlberta T6G 2P4Canada

central sensitization has been associated with chronic pain in whiplash ***:Consecutive whiplash patients were assessed at 3 months post-whiplash injury with the brachial plexus provocation test(BPPT)as a sign of central ***-reported recovery was assessed by the response to the question ‘Do you feel you have recovered fully from your accident injuries?'Results:Sixty-nine subjects(32 males,37 females,age 37.5±13.0 years(mean±SD),range 18-71)were *** these,34 reported a lack of recovery,and 35 reported recovery at 3 months *** mean BPPT elbow extension(from 180°)was 41.5±23.0°,and the mean VAS score for the BPPT was 2.2 ± 1.2(out of 10).Those who reported recovery had a mean BPPT elbow extension angle of 25.1±15.8 while those who did not report recovery had a mean BPPT angle of 58.4 ± 15.9(P＜0.05).The visual analogue scale(VAS)score for recovered subjects was 1.8 ± 1.1 and 2.7 ± 1.1(P＜0.05)for *** was a moderate correlation between self-reported recovery and BPPT elbow extension angle(-0.44)and a lower correlation between self-reported recovery and VAS score(-0.30).Conclusion:Self-reported recovery correlates well with a lower likelihood of signs of central ***(c)2012,Shanghai University of *** and hosting by Elsevier *** rights reserved.

关键词： Brachial plexus provocation test central sensitization Self-reported recovery Whiplash injury

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central sensitization in hypothalamic arcuate nucleus induced by peripheral inflammation

Central sensitization in hypothalamic arcuate nucleus induce...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Jian-Ming PENG,Xiao-Yong LI,Ning-Ang LIU,Wei LI,Long-Sheng XU,Xing-Hong JIANG~* Key Laboratory of Pain Basic Research & Clinical Therapy,Department of Neurobiology and Institute of Neuroscience,Medical College of Soochow University,Suzhou 215123,China

＜正＞Objective In recent years great progress has been made in the study of central sensitization of nociceptive neurons in the spinal cord,in which the glutamate NMDA receptor plays a pivotal *** less is known about sensitization in the supraspinal centers related to the pain *** aim of this study was to test whether central sensitization can be induced in nociceptive neurons in the hypothalamic arcuate nucleus by peripheral inflammation, which is known to be one supraspinal component of the endogenous pain-modulating *** Peripheral inflammation was induced by plantar injection of complete Freund’s adjuvant（CFA）into the hind paw of *** unit neuronal activity was recorded from the arcuate nucleus（ARC）in the slice of mediobasal hypothalamus as well as in anesthetized *** following inflammation was measured by behavioral paw withdrawal responses. The function of NMDA receptor in ARC was detected by Western blot *** receptor antagonists and kinase inhibitors were used to analyze the underlying mechanisms of signal transduction *** Behavioral measurement confirmed a definite hyperalgesia following peripheral *** sensitization was found in ARC as evidenced by（1）significant increase in the frequency of spontaneous unit discharge of ARC neurons from brain slice of inflamed rats,as well as from anesthetized inflamed rats,as compared to the control rats;（2）enhancement of responses of ARC neurons to glutamate and NMDA application in slice of inflamed rats,and the responses of ARC neurons to non-noxious and noxious stimulation in anesthetized inflamed rats were enhanced as ***-regulated expression of phospho-NRl and phospho-NR2B subunit,rather than NR1 and NR2B,was observed in ARC of inflamed ***-ARC microinjection of MK-801（NMDA receptor antagonist）,Ro25-6981 （NR2B subunit antagonist）,CNQX（non-NMDA receptor antagonist）and PP2（Src protein tyrosine kinase selective inhibitor）

关键词： hypothalamic arcuate nucleus central sensitization hyperalgesia NMDA receptor,NR2B subunit Src tyrosine kinase inflammation

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IL-17 may contribute to central sensitization by promoting the proliferation of astrocytes and secretion of proinflammatory cytokines in spinal nerve ligation-induced neuropathic pain

IL-17 may contribute to central sensitization by promoting t...

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第十届全国免疫学学术大会

作者： Sun Caixia Zhaoliang Su Huaxi Xu Jiangsu University

central sensitiztion has been applied to explain neuropathic pain,although its mechanism has not been well *** damage can cause activity-dependent central sensitization,however,central sensitization of neuropathic pain is mostly led by glia cells activation,peripheral immune cells infiltration and chronic nerve ***,infiltrated Th17 cells in CNS have been shown to be involved in autoimmune diseases with neuropathic pain,such as multiple sclerosis and experimental autoimmune encephalomyelitis(EAE).In this study,based on the rat model of spinal nerve ligation was established,we analyzed the Th17 cells infiltration in spinal cord during the maintenance phase of neuropathic pain,and explored the relationship between infiltrated Th17 cells and activated *** results showed that the infiltrated CD4+T cells in spinal cord were increased in the rat model of spinal nerve ligation,and further immunofluorescence staining displayed that the Th17 cells were located at superficial laminae of spinal dorsal horn,it was accompanied by significant up-regulated IL-17,RORγt,CCL2 and CCL20 m ***,the m RNA expression of IL-1βand IL-6 was also significantly enhanced in model rats comparing with sham and control groups in the spinal dorsal *** vitro,the ability of proliferation and secretion of proinflammatory cytokines were obviously increased in the IL-17 stimulated astrocytes isolated from the model of spinal nerve ligation-induced neuropathic *** data indicates that the IL-17 secreted by Th17 cells may contribute to central sensitization through promoting the proliferation of astrocytes and secretion of proinflammatory cytokines in rat mode of spinal nerve ligation-induced neuropathic pain.

关键词： Neuropathic pain central sensitization IL-17 Model of spinal nerve ligation Rat

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System A transporters in spinal cord is involved in central sensitization induced by formalin in rat

System A transporters in spinal cord is involved in central ...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Jing WANG~1,Bin GEN~1,Tian-Cheng WANG~2,Ya-Yi XIA~1,Hai-Li SHEN~3,Zhi-Ping WANG~(4,*) 1 Institute of Orthopaedics,Lanzhou University Second Hospital,Lanzhou 730030,China 2 Department of Neurology,Lanzhou University Second Hospital,Lanzhou 730030,China 3 Department of Pain,Lanzhou University Second Hospital,Lanzhou 730030,China 4 Department of urology,Lanzhou University Second Hospital,Lanzhou 730030,China

＜正＞Objective There is evidence that glia-neuron interactions are involved in mechanisms underlying the development of chronic *** sensitization is a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation and is considered a crucial process underlying the development and maintain of chronic pain *** is growing evidence that astroglia play an important role in chronic *** plays a major role in central sensitization and astrocyte-neuronal glutamate-glutamine cycle is involved in central sensitization in the spinal *** A transport is responsible for the accumulation of glutamine by neurons and non-metabolised amino acid analogue a-（methylamino）isobutyric acid（MeAIB）appears to be a specific inhibitor of all isoforms of this *** current study investigated the roles of System A transport in inhibition of central sensitization induced by formalin in *** A total of 43 male,Sprague Dawley rats,aged 4 months,were randomly assigned to a sham operation group（n=6）and a model group（n= 37）.Rats in the model group received intrathecal infusion operation at spinal cord.7 days later,37 model rats were randomly divided into saline,MeAIB 0.05 mM,MeAIB 0.1 mM,MeAIB 0.3 mM,MeAIB 0.5 mM,and MeAIB 1.0 mM and formalin subcutaneous injection alone *** 15 min after intrathecal injection,a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5%formalin（50μL）in the left hindpaw. After the completion of behavioral measurements,rats were sacrifice and the spinal cords were removed for GFAP immunohistochemistry *** In this study,intrathecal injection MeAIB produced a dose-dependent inhibition of inflammatory pain,including nociceptive behaviors and GFAP expression in the spinal dorsal *** control experiments,intraplantar injection of formalin alone or intrathecal injection of saline did not produce a

关键词： system A transport glutamate-glutamine shuttle central sensitization inflammatory pain spinal cord

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Recent advances in the understanding and management of chronic pancreatitis pain

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Journal of Pancreatology 2024年第1期7卷 35-44页

作者： Jessica Walker Olivia L.Babyok Jami L.Saloman Anna Evans Phillips Department of Internal Medicine University of Pittsburgh Medical CenterPittsburghPAUnited States Division of Gastroenterology Hepatology and NutritionDepartment of MedicineSchool of MedicineUniversity of PittsburghPittsburghPAUnited States Center for Pain Research Center for NeuroscienceSchool of MedicineUniversity of PittsburghPittsburghPAUnited States

Abdominal pain is the most common symptom of chronic pancreatitis(CP)and is often debilitating for patients and very difficult to *** date,there exists no cure for the *** strategies focus on symptom management and on mitigation of disease progression by reducing toxin exposure and avoiding recurrent inflammatory *** treatment protocols start with medical management followed by consideration of procedural or surgical intervention on selected patients with severe and persistent *** incorporation of adjuvant therapies to treat comorbidities including psychiatric disorders,exocrine pancreatic insufficiency,mineral bone disease,frailty,and malnutrition,are in its early *** clinical studies and animal models have been designed to improve investigation into the pathophysiology of CP pain,as well as to improve pain *** the array of tools available,many therapeutic options for the management of CP pain provide incomplete *** still remains much to discover about the neural regulation of pancreas-related *** this review,we will discuss research from the last 5 years that has provided new insights into novel methods of pain phenotyping and the pathophysiology of CP *** discoveries have led to improvements in patient selection for optimization of outcomes for both medical and procedural management,and identification of potential future therapies.

关键词： central sensitization Chronic pancreatitis Pain phenotyping Peripheral sensitization

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High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic postischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord

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Neural Regeneration Research 2023年第11期18卷 2535-2544页

作者： Xin Jia Ziyang Li Xiafeng Shen Yu Zhang Li Zhang Ling Zhang Department of Neurology and Neurological Rehabilitation Shanghai Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center)School of MedicineTongji UniversityShanghaiChina Department of Rehabilitation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiChina Key Laboratory of Cellular Physiology(Shanxi Medical University) Ministry of Educationand the Department of PhysiologyShanxi Medical UniversityTaiyuanShanxi ProvinceChina Key Laboratory of central CNS Regeneration(Ministry of Education) Guangdong-Hong Kong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong ProvinceChina

Physical exe rcise effectively alleviates chronic pain associated with complex regional pain syndrome type-Ⅰ.However,the mechanism of exe rcise-induced analgesia has not been *** studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous ***,whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-Ⅰ has not been *** the present study,a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-Ⅰ and subjected to an intervention involving swimming at different *** pain was reduced only in mice that engaged in high-intensity *** resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain,while high-intensity swimming restored expression of resolvin E1 and chemerin receptor ***,shRNA-mediated silencing of chemerin receptor 23in the spinal cord reve rsed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammato ry pola rization of microglia in the dorsal horn of the spinal *** findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.

关键词： central sensitization chemerin receptor 23 chronic post-ischemia pain complex regional pain syndrome exercise-induced analgesia microglia neuroinflammation resolvin E1 spinal cord swimming

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TNF-αTNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and central Mechanisms

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Neuroscience Bulletin 2018年第1期34卷 42-53页

作者： Xiuhua Miao Ya Huang Teng-Teng Liu Ran Guo Bing Wang Xue-Long Wang Li-Hua Chen Yan Zhou Ru-Rong Ji Tong Liu The Affiliated Zhangjiagang Hospital of Soochow University Zhangjiagang 215600 China Institute of Neuroscience Soochow University Suzhou 215021 China Capital Medical University Electric Power Teaching Hospital Beijing 100073 China Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Department of Nutrition and Food Hygiene School of Public Health Soochow University Suzhou 215123 China Department of Anesthesiology Duke University Medical Center Durham NC 27710 USA Department of Neurobiology Duke University Medical Center Durham NC 27710 USA

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.

关键词： Itch Tumor necrosis factor Tumor necrosis factor receptor Spinal cord central sensitization

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Astroglial glutamate-glutamine cycle is involved in the modulation of inflammatory nociception in rats

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Neural Regeneration Research 2011年第35期6卷 2746-2750页

作者： Tiancheng Wang Jing Wang Bin Geng Hongyu Guo Haili Shen Yayi Xia Department of Neurology Second Hospital of Lanzhou University Lanzhou University Lanzhou 730030 Gansu Province China Institute of Orthopedics Second Hospital of Lanzhou University Lanzhou University Lanzhou 730030 Gansu Province China Department of Obstetrics and Gynecology Second Hospital of Lanzhou University Lanzhou University Lanzhou 730030 Gansu Province China Department of Pain Second Hospital of Lanzhou University Lanzhou University Lanzhou 730030 Gansu Province China

Our previous behavioral studies have indicated that the astroglial glutamate-giutamine cycle is involved in the process of formalin-induced spinal cord central sensitization, but there was little morphological evidence. In this study, double-labeling immunofluorescence techniques showed that after rats were intrathecally injected with PBS and plantarly injected with formalin, glial fibrillary acidic protein （GFAP） and glutamine synthesase （GS） expression were increased and GFAP/GS coexpression was changed to include layers III and IV. After intrathecal injection of methionine sulfoximine, a GS specific inhibitor, the formalin-induced change in expression and coexpression of GFAP and GS in spinal cord dorsal horns was inhibited. The morphology, distribution and quantity of astrocytes recovered to normal levels. An intrathecal glutamine injection reversed the inhibitory effect of methionine sulfoximine. Astrocytes showed significant activation and distribution extended to layers V and VI. The present study provides morphological evidence that the astroglial glutamateglutamine cycle is involved in the process of formalin-induced spinal cord central sensitization.

关键词： astrocyte glutamate-glutamine cycle central sensitization immunohistochemistry

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Systematic mechanism-orientated approach to chronic pancreatitis pain

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World Journal of Gastroenterology 2015年第1期21卷 47-59页

作者： Stefan AW Bouwense Marjan de Vries Luuk TW Schreuder Soren S Olesen Jens B Frokjær Asbjorn M Drewes Harry van Goor Oliver HG Wilder-Smith Pain and Nociception Neuroscience Research Group Department of SurgeryRadboud University Medical Center6500HB GelderlandThe Netherlands Department of Gastroenterology and Hepatology and Clinical Medicine Aalborg University Hospital9100 AalborgDenmark Center for Sensory-Motor Interaction Department of Health Science and TechnologyAalborg University9100 AalborgDenmark Department of Anaesthesiology Pain and Palliative MedicineRadboud University Medical Center6500HB GelderlandThe Netherlands

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar *** causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic ***,CP pain continues to be a major clinical *** is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain *** this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically *** central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance *** techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain *** present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms *** research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and *** we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.

关键词： Chronic pancreatitis Pain Pain treatment central sensitization Quantitative sensory testing Electroencephalograpy Magnetic resonance imaging

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