Neuronal-Glia Interactions in Trigeminal Ganglia as a Basis for Future Therapy

三叉神经节中神经元-胶质细胞的相互作用作为未来治疗的基础

• 批准号: 8661746
• 负责人: LI-YEN M HUANG
• 金额: $ 38.7万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661746
• 关键词: Afferent Neurons; Behavior; Biological Assay; Bioluminescence; Brain; Cell Communication; Chemicals; Co-Immunoprecipitations; Communication; Development; Disease; Down-Regulation; Dyes; Enzyme-Linked Immunosorbent Assay; Exocytosis; Feedback; Frequencies; Future; Ganglia; Generations; Genetic; Goals; Grant; Image; Image Analysis; Inflammation; Injection of therapeutic agent; Injury; Ions; Knowledge; Ligation; Luciferases; Maintenance; Measures; Mediating; Monitor; Mutant Strains Mice; Nerve; Neuroglia; Neurons; Nociception; Pain; Pain Disorder; Pain management; Pathway interactions; Phase; Play; Public Health; Rattus; Recombinants; Role; Sensory; Skin; Spinal Ganglia; Structure of trigeminal ganglion; Synapses; Techniques; Therapeutic; Time; Up-Regulation; Viral; Viscera; adeno-associated viral vector; afferent nerve; base; chronic pain; cytokine; design; injured; nerve injury; neuronal cell body; pain behavior; public health relevance; receptor; response; sciatic nerve; sensory system; small hairpin RNA; somatosensory; therapeutic target; treatment strategy; two-photon

DESCRIPTION (provided by applicant): Our recent studies of the communication between neuronal soma and satellite glial cells (SGCs) in dorsal root ganglia (DRGs) suggest that somatic release of ATP in response to afferent nerve stimulation activates purinergic P2X7 receptors (P2X7Rs) in SGCs. Under normal conditions, tonic activation of P2X7Rs in SGCs reduces P2X3R expression in neuronal somata, thus exerting inhibitory control of neuronal activity. Following high frequency nerve stimulation, activation of P2X7Rs evokes cytokine release causing an enhancement of P2X3R activity in somata and an increase in the excitability of neurons. The P2X7R-mediated SGC-neuronal soma feedback controls under inflammation and nerve injury conditions have not been well established. This knowledge is essential for understanding the generation and maintenance of abnormal chronic pain. The goal of this application is to understand changes in neuronal soma-SGC communication during different phases of chronic pain development. We hypothesize that following injury, an increase in cytokine release switches P2Rmediated SGC-soma communication from inhibitory to excitatory feedback control, thus initiating the development of abnormal pain states. A subsequent large increase in ATP release, which activates P2X7Rs and pannexin-1, produces a large enhancement of SGC-soma communication and thus leads to the transition from the development to the maintenance phase of chronic pain. We will (1) determine if P2R-mediated SGC-soma communication changes during the development and maintenance phase of chronic pain, (2) determine the mechanisms underlying the change in SGC-soma communication and (3) determine if modulation of SGC-soma communication is a valid strategy for the management of chronic pain.

描述(申请人提供)：我们最近对背根神经节(DRGs)神经元胞体和卫星胶质细胞(SGCs)之间的通讯的研究表明，躯体对传入神经刺激的ATP释放激活了SGCs中的嘌呤能P2X7受体(P2X7Rs)。在正常情况下，SGCs中的P2X7Rs的紧张性激活减少了神经元胞体中的P2X3R的表达，从而对神经元的活动起到抑制控制作用。在高频神经刺激后，P2X7Rs的激活引起细胞因子的释放，导致躯体中的P2X3R活性增强，神经元的兴奋性增加。在炎症和神经损伤条件下，P2X7R介导的SGC-神经元胞体反馈调控机制尚未得到很好的证实。这一知识对于理解异常慢性疼痛的产生和维持是必不可少的。这个应用程序的目标是了解慢性疼痛发展的不同阶段神经元胞体-SGC通讯的变化。我们假设在损伤后，细胞因子释放开关P2R介导的SGC-Soma通信从抑制性反馈控制到兴奋性反馈控制，从而启动异常疼痛状态的发展。随后，激活P2X7Rs和pAnnexin-1的ATP释放大幅增加，导致SGC-Soma的通讯大大增强，从而导致慢性疼痛从发展阶段过渡到维持阶段。我们将(1)确定P2R介导的SGC-SOMA通信是否在慢性疼痛的发展和维持阶段发生变化，(2)确定SGC-SOMA通信变化的潜在机制，(3)确定SGC-SOMA通信的调制是否是治疗慢性疼痛的有效策略。