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

• 批准号: 8037678
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037678
• 关键词: Address; Affect; Agonist; Awareness; Behavior; Behavioral; Brain Stem; Cells; Chemicals; Development; Disease; Etiology; Event; Excision; Excitatory Amino Acids; Exhibits; Freund' s Adjuvant; Glutamate Receptor; Goals; Hippocampus (Brain); Hyperalgesia; Immune; Immune system; Immunohistochemistry; Immunoprecipitation; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-12; 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; Public Health; 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

DESCRIPTION (provided by applicant): 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 posit 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 cytokine IL-12. 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 astroglial activation in the RVM and associated IL-12 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 descending facilitation 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 IL-12 signaling. The outcome of these studies will enhance understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain. Public Health Significance: 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 understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain.

描述（由申请人提供）：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。虽然现在广泛认识到神经胶质和炎性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，但连接免疫和神经元功能的潜在机制尚不清楚。我们拟采用大鼠后爪炎性疼痛模型，研究胶质细胞、细胞因子和神经元之间的相互作用，并探讨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的意义。最近的研究表明，脑干下行回路可以有力地促进疼痛处理，这一过程有助于慢性疼痛状况的发展。损伤后的异常疼痛与延髓头端腹内侧（RVM）神经元活动增强有关，RVM是下行疼痛调制的关键结构。新兴的文献强烈暗示了神经胶质细胞和炎性细胞因子在痛觉过敏的发展中的作用。通过仍然未知的机制，胶质细胞可以在损伤后被激活并释放调节神经元活动的化学介质。这种胶质细胞-细胞因子-神经元相互作用在慢性疼痛过程中可能是至关重要的。到目前为止，还没有研究涉及胶质细胞和相关化学物质在持续性疼痛的下行易化。我们建议确定的细胞和分子机制的下行疼痛促进组织损伤后，强调在RVM电路的神经元-胶质细胞的相互作用。我们认为：1）外周炎症诱导RVM回路中的神经元可塑性，涉及胶质细胞的活化; 2）RVM胶质细胞活化和炎性细胞因子释放通过与神经元N-甲基-D-天冬氨酸受体（NMDAR）的相互作用促进神经元可塑性，并有助于痛觉过敏的下行促进。目的1将检验炎症后RVM中的胶质细胞被激活并通过释放炎性细胞因子IL-12影响神经元功能的假设。将完全弗氏佐剂注射到后爪中以产生炎症和行为痛觉过敏。目的2将确定神经元到胶质细胞的信号传导是否在炎症后的胶质细胞活化中起作用。目的3将检验RVM中的星形胶质细胞活化和相关的IL-12释放通过与神经元NMDAR相互作用促进神经元可塑性并在痛觉过敏的发展中起关键作用的假设。因此，我们提出了一个模型的互惠神经元-胶质细胞的相互作用，在持续性疼痛的下行促进。从以前的研究进展，该模型强调通过损伤产生的神经元输入，伴随的细胞因子释放和NMDAR通过IL-12信号传导的翻译后调节来激活胶质细胞。这些研究的结果将增强对免疫和神经系统之间功能联系的理解，并有助于确定用于管理慢性疼痛的新靶点和药物。公共卫生意义：我们建议采用大鼠炎症性疼痛模型来研究胶质细胞，细胞因子和神经元之间的相互作用，并探讨其在中枢神经系统对损伤的反应和持续性疼痛条件的发展中的意义。虽然现在广泛认识到神经胶质和炎性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，但连接免疫和神经元功能的潜在机制在很大程度上是未知的。这些研究的结果将增强对免疫和神经系统之间功能联系的理解，并有助于确定用于管理慢性疼痛的新靶点和药物。