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: 7530384
• 负责人: KE REN
• 金额: $ 32.81万
• 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/7530384
• 关键词: Address; Affect; Agonist; Astrocytes; Awareness; Behavior; Behavioral; Brain Stem; Cells; Chemicals; Chromosome Pairing; Chronic; Condition; Development; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Excision; Excitatory Amino Acids; Exhibits; Freund' s Adjuvant; GLAST Protein; Glial Fibrillary Acidic Protein; Glutamate Receptor; Glutamate Transporter; Glutamate-Ammonia Ligase; Goals; Hippocampus (Brain); Hyperalgesia; Immune; Immunohistochemistry; Immunoprecipitation; Immunotoxins; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-12; Interleukins; Lead; Learning; Link; Literature; Local anesthesia; Long-Term Depression; Long-Term Potentiation; Macrophage-1 Antigen; Magnesium; Maintenance; Mediator of activation protein; Memory; Methionine Sulfoximine; Microglia; Minocycline; 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; Proteins; Public Health; Rattus; Receptor Activation; Receptor Signaling; Research Design; Rheumatism; Role; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Slice; Staging; Stimulus; Stroke; Structure; Structure of trigeminal nerve spinal tract nucleus; Study models; Substance P Receptor; Synapses; Testing; Thinking; Time; Tissue Model; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ursidae Family; Western Blotting; Work; Yang; anakinra; central sensitization; chemical release; chronic pain; cytokine; fluorocitrate; functional mimics; human TNF protein; inflammatory pain; inhibitor/antagonist; neural circuit; novel; orofacial; painful neuropathy; propentofylline; 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)：人们对神经免疫相互作用及其在中风、帕金森氏病和慢性疼痛等疾病的病因中的作用的认识越来越多。虽然现在人们普遍认识到胶质细胞和炎性细胞因子通过各种细胞信号通路影响神经元的功能和行为，但免疫和神经元功能之间的潜在机制尚不清楚。我们建议使用大鼠后爪炎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，并探讨它们在中枢神经系统对损伤的反应和持续性疼痛发展中的意义。最近的研究表明，脑干下行回路可以有力地促进疼痛的处理，这一过程有助于慢性疼痛的发展。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。新出现的文献强烈暗示神经胶质细胞和炎性细胞因子在痛觉过敏的发展中所起的作用。通过尚不清楚的机制，神经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-神经元的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，还没有研究表明胶质细胞和相关化学物质参与了持续性疼痛的下行促进作用。我们建议确定组织损伤后促进下行疼痛的细胞和分子机制，重点是RVM回路中神经元-神经胶质细胞的相互作用。我们认为：1)外周炎症可诱导RVM回路中的神经元可塑性，涉及胶质细胞的激活；2)RVM的胶质细胞激活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验证炎症后右室神经胶质细胞被激活，并通过释放炎性细胞因子IL-12影响神经元功能的假说。完全的弗氏佐剂将被注射到后爪，以产生炎症和行为痛敏。目的2将确定神经元到胶质细胞的信号是否在炎症后的胶质细胞激活中发挥作用。目的3验证RVM中星形胶质细胞的激活及其相关的IL-12释放通过与神经元NMDAR的相互作用促进神经元可塑性的假说，并在痛觉过敏的发展中发挥关键作用。因此，我们提出了持续性疼痛下行易化过程中神经元-神经胶质细胞相互作用的模型。与以前的研究相比，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以及通过IL-12信号对NMDAR的翻译后调节来激活胶质细胞。这些研究的结果将加强对免疫和神经系统之间功能联系的了解，并有助于确定治疗慢性疼痛的新靶点和药物。公共卫生意义：我们建议使用炎症性疼痛的大鼠模型来研究胶质细胞、细胞因子和神经元之间的相互作用，并探讨它们在中枢神经系统对损伤的反应和持续性疼痛条件发展中的意义。虽然现在人们普遍认识到胶质细胞和炎性细胞因子通过各种细胞信号通路影响神经元的功能和行为，但免疫和神经元功能之间的潜在机制在很大程度上还不清楚。这些研究的结果将加强对免疫和神经系统之间功能联系的了解，并有助于确定治疗慢性疼痛的新靶点和药物。