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Glial-cytokine-neuronal interactions in neuropathic pain

神经病理性疼痛中神经胶质细胞因子神经元的相互作用

基本信息

批准号：
8304998
负责人：
Han-Rong Weng
金额：
$ 28.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304998
关键词：
AMPA Receptors Accounting Acute Pain Aftercare Astrocytes Behavior Behavioral Carrier Proteins Cells Data Development Down-Regulation Enzyme-Linked Immunosorbent Assay Excision Figs - dietary Functional disorder Glutamate Receptor Glutamate Transporter Glutamates Goals Health Hyperalgesia Hypersensitivity Immunohistochemistry Inflammatory Interleukin Activation Interleukin-3 Interleukins Lead Ligation Maintenance Mediating Mediator of activation protein Microglia Minocycline Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate Neuroglia Neurons Neuropathy Nociception Operative Surgical Procedures Outcome Pain Pathogenesis Patients Peripheral Peripheral nerve injury Pharmacology Presynaptic Terminals Property Prosencephalon Rattus Role Signal Transduction Signal Transduction Pathway Slice Specific qualifier value Spinal Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Time Tumor Necrosis Factor-alpha Voltage-Clamp Technics base behavior test chemotherapy chronic pain cytokine dorsal horn improved inhibitor/antagonist insight nerve injury painful neuropathy postsynaptic presynaptic propentofylline protein expression receptor research study sciatic nerve spatiotemporal transmission process uptake voltage clamp

项目摘要

Description (provided by applicant): How dysfunctional glial cells lead to abnormal pain signaling in the spinal dorsal horn in neuropathic pain remains a mystery. Activation of glutamate receptors by glutamate is a key step for acute pain transmission and activation of signal transduction pathways leading to initiation and maintenance of pathological pain. Activation of glutamate receptors is governed by three essential factors: the amount of synaptically released glutamate, the rate at which glutamate is removed by glutamate transporters (GTs) and the properties of postsynaptic glutamate receptors. Modern pain treatments directed at the transmission of pain singals have mainly focused either on the presynaptic levels to block glutamate release from presynaptic terminals or on the postsynaptic levels to block glutamate receptors and glutamate activated signal transduction pathways in postsynaptic neurons. Targeting at GTs to correct abnormal activation of glutamate receptors has been much less investigated. One key role for glial cells in regulating signal transmission at the glutamatergic synapse is the removal of synaptic glutamate by glial GTs. Studies on the forebrain have demonstrated that glial GT accounts for more than 94% of all CNS synaptic glutamate uptake and is a key machinery regulating synaptic signal transmission and plasticity. However, the role of glial GTs in regulating synaptic transmission in the spinal dorsal horn and their contribution to abnormal pain signaling have not been established. Based on our preliminary findings, we hypothesize that activation of glial cells induced by nerve injury results in dysfunction of glial GTs, which leads to abnormal activation of ionotropic glutamate receptors in the spinal dorsal horn and behavioral hypersensitivity. This hypothesis will be tested with three specific aims. Specific Aim 1 will determine the relationships between glial GT expression and development of behavioral hypersensitivity, glial activation and release of pro-inflammatory cytokines induced by nerve injury. Specific Aim 2 will determine the contribution of deficient glutamate uptake by glial GTs to abnormal activation of AMPA and NMDA receptors in the spinal dorsal horn and behavioral hypersensitivity in neuropathic rats. Specific Aim 3 will determine the contribution of recovered glutamate uptake by glial GTs to the "normalized" activation of ionotropic glutamate receptors in the spinal dorsal horn and to the "normalized" nociceptive behaviors in neuropathic rats after treatments of glial inhibitors or antagonists for pro-inflammatory cytokines. Experiments will be conducted in control (normal naove and sham operated) rats and neuropathic rats induced by partial sciatic nerve ligation, which is known to mimic neuropathic pain induced by partial nerve injury in patients. Multi-disciplinary- techniques, including visualized whole cell voltage clamp recordings from spinal slices, pharmacology, immunohistochemistry and behavioral tests will be applied to test our hypothesis. The proposed study will provide new insights into the synaptic and molecular mechanisms underlying glial-cytokine-neuronal interactions in neuropathic pain and may potentially lead to the use of GTs as a new target for reducing persistent and abnormal activation of glutamate receptors in the management of chronic pain. PUBLIC HEALTH RELEVANCE: How dysfunctional glial cells lead to abnormal pain signaling in the spinal dorsal horn in neuropathic pain remains a mystery. Activation of glutamate receptors by glutamate is a key step for acute pain transmission and activation of signal transduction pathways leading to initiation and maintenance of pathological pain. We hypothesize that activation of glial cells induced by nerve injury results in dysfunction of glial GTs, which leads to abnormal activation of ionotropic glutamate receptors in the spinal dorsal horn and behavioral hypersensitivity. 1

描述（由申请人提供）：功能失调的神经胶质细胞如何导致神经性疼痛中脊髓背角的疼痛信号异常仍然是个谜。谷氨酸对谷氨酸受体的激活是急性疼痛传递和信号转导途径激活导致病理性疼痛发生和维持的关键步骤。谷氨酸受体的激活由三个基本因素控制：突触释放谷氨酸的量、谷氨酸转运蛋白（GT）去除谷氨酸的速率以及突触后谷氨酸受体的特性。针对疼痛信号传递的现代疼痛治疗主要集中在突触前水平以阻断突触前末梢释放谷氨酸，或集中在突触后水平以阻断突触后神经元中谷氨酸受体和谷氨酸激活的信号转导途径。针对 GT 来纠正谷氨酸受体异常激活的研究较少。神经胶质细胞在调节谷氨酸能突触信号传递中的一项关键作用是通过神经胶质 GT 去除突触谷氨酸。对前脑的研究表明，神经胶质GT占所有中枢神经系统突触谷氨酸摄取的94%以上，是调节突触信号传递和可塑性的关键机制。然而，神经胶质 GT 在调节脊髓背角突触传递中的作用及其对异常疼痛信号传导的贡献尚未确定。基于我们的初步研究结果，我们假设神经损伤诱导的神经胶质细胞活化导致神经胶质GTs功能障碍，从而导致脊髓背角离子型谷氨酸受体的异常激活和行为超敏反应。该假设将通过三个具体目标进行检验。具体目标 1 将确定神经胶质 GT 表达与神经损伤引起的行为超敏反应、神经胶质活化和促炎细胞因子释放之间的关系。具体目标 2 将确定神经胶质 GT 摄取谷氨酸不足对脊髓背角 AMPA 和 NMDA 受体异常激活以及神经病大鼠行为超敏反应的影响。具体目标 3 将确定神经胶质 GT 恢复的谷氨酸摄取对脊髓背角离子型谷氨酸受体“正常化”激活的贡献，以及对神经病性大鼠在神经胶质抑制剂或促炎细胞因子拮抗剂治疗后“正常化”伤害性行为的贡献。实验将在对照（正常的幼鼠和假手术）大鼠和部分坐骨神经结扎诱导的神经病变大鼠中进行，已知结扎部分坐骨神经可以模拟患者部分神经损伤引起的神经病理性疼痛。多学科技术，包括脊髓切片的可视化全细胞电压钳记录、药理学、免疫组织化学和行为测试，将用于检验我们的假设。拟议的研究将为神经性疼痛中神经胶质-细胞因子-神经元相互作用的突触和分子机制提供新的见解，并可能导致使用 GT 作为减少慢性疼痛治疗中谷氨酸受体持续和异常激活的新靶点。公共卫生相关性：功能失调的神经胶质细胞如何导致神经性疼痛中脊髓背角的疼痛信号异常仍然是个谜。谷氨酸对谷氨酸受体的激活是急性疼痛传递和信号转导途径激活导致病理性疼痛发生和维持的关键步骤。我们假设神经损伤诱导的神经胶质细胞激活导致神经胶质GTs功能障碍，从而导致脊髓背角离子型谷氨酸受体的异常激活和行为超敏反应。 1