Glial-cytokine-neuronal interactions in the mechanisms of persistent pain

持续性疼痛机制中的胶质细胞因子神经元相互作用

基本信息

批准号：
8247023
负责人：
KE REN
金额：
$ 32.16万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247023
关键词：
Address Affect Agonist Awareness Behavior Behavioral Brain Stem Cells Chemicals Cytokine Signaling Development Disease Etiology Event Excision Excitatory Amino Acids Exhibits Freund&apos s Adjuvant Glutamate Receptor Goals Hippocampus (Brain)Hyperalgesia Immune Immune system Immunohistochemistry Immunoprecipitation In Vitro Inflammation Inflammatory Injection of therapeutic agent Injury Interleukin-1 Interleukins Lead Learning Link Literature Local anesthesia Long-Term Depression Long-Term Potentiation Magnesium Maintenance Mediator of activation protein Memory Microglia Modeling Molecular Multiple Sclerosis N-Methyl-D-Aspartate Receptors Nerve Nervous system structure Neuraxis Neuroglia Neuronal Plasticity Neurons Neuropharmacology Neurotransmitters Outcome Study Pain Pain management Parkinson Disease Peripheral Persistent pain Phosphorylation Play Post-Translational Regulation Preparation Process Rattus Receptor Activation Research Design Rheumatism Role Series Signal Pathway Signal Transduction Signal Transduction Pathway Site Slice Source Staging Stimulus Stroke Structure Study models Substance P Receptor Synapses Testing Time Tissue Model Tissues Tumor Necrosis Factor-alpha Ursidae Family Western Blotting Work active control central sensitization chemical release chronic pain cytokine functional mimics inflammatory pain inhibitor/antagonist neural circuit novel painful neuropathy receptor research study response to injury voltage

项目摘要

There has been increasing awareness of neuroimmune interactions and their role in the etiology of diseases including stroke, Parkinson's disease, and chronic pain. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are unknown. We propose to employ a rat model of hind paw inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain. Recent studies indicate that pain processing can be vigorously facilitated by brainstem descending circuitry, a process that contributes to the development of chronic pain conditions. Abnormal pains after injury are linked to an enhanced neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. The emerging literature strongly implicates a role for glia and inflammatory cytokines in the development of hyperalgesia. Through still unknown mechanisms, glia can be activated after injury and release chemical mediators that modulate neuronal activity. Such glial-cytokine-neuronal interactions may be critical in the chronic pain process. To date, no studies have addressed the involvement of glia and related chemicals in descending facilitation of persistent pain. We propose to identify the cellular and molecular mechanisms of descending pain facilitation after tissue injury with an emphasis on neuronal-glial interactions in the RVM circuitry. We hypothesize that 1) peripheral inflammation induces neuronal plasticity in the RVM circuitry involving activation of glia; and 2) RVM glial activation and inflammatory cytokine release facilitate neuronal plasticity through interactions with neuronal N-methyl-D-aspartate receptors (NMDAR) and contribute to the descending facilitation of hyperalgesia. Aim 1 will test the hypothesis that glial cells are activated in the RVM after inflammation and affect neuronal function through release of inflammatory cytokines. Complete Freund's adjuvant will be injected into the hind paw to produce inflammation and behavioral hyperalgesia. Aim 2 will determine whether neuron-to-glia signaling plays a role in glial activation after inflammation. Aim 3 will test the hypothesis that glial activation in the RVM and associated cytokine release facilitate neuronal plasticity through interaction with neuronal NMDAR and play a critical role in the development of hyperalgesia. Thus, we have proposed a model of reciprocal neuronal-glial interactions in the development of persistent pain. Advancing from previous studies, the model emphasizes activation of glia by injury-generated neuronal input, concomitant cytokine release, and post-translational regulation of NMDAR through cytokine signaling. The outcome of these studies will enhance our understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain. We propose to employ a rat model of inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain conditions. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are largely unknown. The outcome of these studies will enhance our understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain.

人们越来越认识到神经免疫相互作用及其在疾病病因学中的作用包括中风、帕金森病和慢性疼痛。尽管现在人们普遍认识到神经胶质细胞和炎症细胞因子通过多种细胞信号传导途径影响神经元功能和行为，连接免疫和神经元功能的潜在机制尚不清楚。我们建议雇用一只老鼠后爪炎性疼痛模型，用于研究神经胶质细胞、细胞因子和神经元之间的相互作用并探索它们在中枢神经系统对损伤的反应和持续性疼痛的发展中具有重要意义。最近的研究表明，脑干下行回路可以大力促进疼痛处理，导致慢性疼痛病症发展的过程。受伤后出现异常疼痛是与延髓头侧腹内侧 (RVM) 的神经元活动增强有关，RVM 是大脑中的关键结构下行疼痛调节。新兴文献强烈暗示神经胶质细胞和炎症的作用痛觉过敏发展中的细胞因子。通过仍然未知的机制，神经胶质细胞可以在损伤并释放调节神经元活动的化学介质。这种神经胶质细胞因子神经元相互作用在慢性疼痛过程中可能至关重要。迄今为止，还没有研究探讨过参与神经胶质细胞和相关化学物质对持续性疼痛的下降促进作用。我们建议识别细胞和组织损伤后疼痛减轻的分子机制，重点是神经胶质细胞 RVM 电路中的交互。我们假设 1）外周炎症会诱导神经元可塑性涉及神经胶质细胞激活的 RVM 电路； 2) RVM 胶质细胞激活和炎症细胞因子释放通过与神经元 N-甲基-D-天冬氨酸受体 (NMDAR) 相互作用促进神经元可塑性有助于痛觉过敏的下降促进。目标 1 将检验以下假设：炎症后神经胶质细胞在 RVM 中被激活并影响神经元通过释放炎症细胞因子发挥作用。将弗氏完全佐剂注射到后肢爪子产生炎症和行为痛觉过敏。目标 2 将确定神经元到神经胶质细胞是否信号传导在炎症后的神经胶质细胞激活中发挥作用。目标 3 将检验神经胶质细胞激活的假设 RVM 和相关细胞因子释放通过与神经元相互作用促进神经元可塑性 NMDAR 在痛觉过敏的发生中发挥着关键作用。因此，我们提出了一个在持久性发展过程中神经元-胶质细胞相互作用的模型。疼痛。与之前的研究相比，该模型强调损伤产生的神经元对神经胶质细胞的激活 NMDAR 通过细胞因子信号传导进行输入、伴随细胞因子释放和翻译后调节。这些研究的结果将增强我们对免疫和免疫系统之间功能联系的理解。神经系统并有助于确定治疗慢性疼痛的新靶点和药物。我们建议采用大鼠炎症疼痛模型来研究神经胶质细胞、细胞因子和神经元之间的相互作用。神经元并探讨它们在中枢神经系统对损伤的反应和发展中的重要性持续疼痛的情况。尽管现在人们广泛认识到神经胶质细胞和炎症细胞因子会影响通过多种细胞信号通路的神经元功能和行为，其潜在机制免疫和神经功能之间的联系在很大程度上是未知的。这些研究的结果将增强我们的了解免疫系统和神经系统之间的功能联系并有助于识别新靶点以及治疗慢性疼痛的药物。