Role of Spinal Cord Lamina II Astrocytes in Neurophysiology and Chronic Pain

脊髓层 II 星形胶质细胞在神经生理学和慢性疼痛中的作用

• 批准号: 7385710
• 负责人: Ken Douglas McCarthy
• 金额: $ 28.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385710
• 关键词: Action Potentials; Affect; Appearance; Astrocytes; Brain; Brain Stem; Buffers; Calcium Oscillations; Cells; Chromosome Pairing; Development; Dinoprostone; Elements; Exhibits; Fire - disasters; G-Protein-Coupled Receptors; Genetic; Glutamates; Imaging Techniques; Inflammatory; Lead; Link; Maintenance; Microglia; Modeling; Mus; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neurons; Neuropathy; Nociception; Numbers; Pain; Play; Potassium; Process; Property; Prostaglandins; Regulation; Research; Research Project Grants; Role; Second Messenger Systems; Serine; Signal Transduction; Spinal Cord; Spinal cord posterior horn; Stimulus; Synapses; Testing; Thinking; central sensitization; chronic pain; cytokine; dorsal horn; extracellular; inflammatory pain; nervous system disorder; neuronal excitability; neurophysiology; receptive field; research study; second messenger; tool; transcription factor; uptake

DESCRIPTION (provided by applicant): It has become increasingly evident that astrocytes actively participate in neurophysiology, as well as contribute to the development and progression of a number of neurological disorders. Astrocytes are the most numerous cells in brain and spinal cord (~50% of all CNS cells) and associate with all cellular elements; a single astrocyte can envelop as many as 100,000 synapses. Astrocytes play a critical role in regulating neuronal excitability through their ability to buffer extracellular K+ and take up synaptically released glutamate. Interference with either of these properties leads to neuronal hyperexcitability. Astrocytes also exhibit Gs-, Gi-, and Gq-linked G-protein coupled receptors (GPCRs) regulating a host of second messenger cascades. Increases in astrocytic Ca2+ lead to the release gliotransmitters including glutamate, ATP, PGE2, and D-serine. Each of these gliotransmitters plays an important role in regulating neuronal excitability in the spinal cord and the first three are thought to be involved in the sensitization of nociceptive neurons in chronic pain. Astrocytes exhibit calcium oscillations and intercellular calcium waves that enable them to synchronize neuronal activity through the release of gliotransmitters. Further, reactive astrocytes release a number of factors thought to sensitize nociceptive neurons including NGF, NO, proinflammatory cytokines, and prostaglandins. While research in the field of chronic pain has focused primarily on mechanisms intrinsic to nociceptive neurons, more recent studies suggest that chronic pain derives, in part, from the activation of microglia and astrocytes. Given the prominent role of astrocytes in the regulation of neuronal excitability, it is not surprising that there is an excellent correlation between the development of chronic pain and the appearance of reactive astrocytes. Pharmacological as well as genetic studies indicate that blocking astrocytic activation blocks the maintenance of certain forms of chronic pain. Experiments within this proposal will take advantage of an experimental tool kit composed of electrophysiological and confocal imaging techniques, together with genetically modified lines of mice to study the role of astrocytes in chronic pain. In Specific Aims 1 and 2, we will determine if astrocytic properties known to modulate neuronal excitability are altered in the setting of chronic pain. These studies will include analyses of potassium buffering and glutamate uptake as well as the ability of astrocytes to modulate neuronal excitability through the release of gliotransmitters. It is becoming increasing clear that inflammatory processes are involved in a number of neurological diseases, including chronic pain. In Specific Aim 3 we will test the hypothesis that the activation of astrocytic NF:B, a proinflammatory transcription factor, is important in the development or maintenance of chronic pain.

描述（由申请人提供）：越来越明显的是，星形胶质细胞积极参与神经生理学，并有助于许多神经系统疾病的发生和进展。星形胶质细胞是大脑和脊髓中数量最多的细胞（约占所有中枢神经系统细胞的 50%），并与所有细胞成分相关；单个星形胶质细胞可以包裹多达 100,000 个突触。星形胶质细胞通过缓冲细胞外 K+ 和吸收突触释放的谷氨酸的能力，在调节神经元兴奋性方面发挥着关键作用。干扰这些特性中的任何一个都会导致神经元过度兴奋。星形胶质细胞还表现出 Gs、Gi 和 Gq 连接的 G 蛋白偶联受体 (GPCR)，调节大量第二信使级联。星形细胞 Ca2+ 的增加导致神经胶质递质的释放，包括谷氨酸、ATP、PGE2 和 D-丝氨酸。这些神经胶质递质中的每一种在调节脊髓神经元兴奋性中都发挥着重要作用，前三种被认为与慢性疼痛中伤害性神经元的敏化有关。星形胶质细胞表现出钙振荡和细胞间钙波，使它们能够通过释放胶质递质来同步神经元活动。此外，反应性星形胶质细胞释放许多被认为可使伤害性神经元敏感的因子，包括 NGF、NO、促炎细胞因子和前列腺素。虽然慢性疼痛领域的研究主要集中在伤害性神经元固有的机制上，但最近的研究表明，慢性疼痛部分源于小胶质细胞和星形胶质细胞的激活。鉴于星形胶质细胞在神经元兴奋性调节中的突出作用，慢性疼痛的发展与反应性星形胶质细胞的出现之间存在极好的相关性也就不足为奇了。药理学和遗传学研究表明，阻断星形胶质细胞的激活可以阻止某些形式的慢性疼痛的维持。该提案中的实验将利用由电生理学和共聚焦成像技术组成的实验工具包以及转基因小鼠品系来研究星形胶质细胞在慢性疼痛中的作用。在具体目标 1 和 2 中，我们将确定已知的调节神经元兴奋性的星形细胞特性是否在慢性疼痛的情况下发生改变。这些研究将包括分析钾缓冲和谷氨酸吸收以及星形胶质细胞通过释放胶质递质调节神经元兴奋性的能力。越来越清楚的是，炎症过程与许多神经系统疾病有关，包括慢性疼痛。在具体目标 3 中，我们将检验以下假设：星形细胞 NF:B（一种促炎转录因子）的激活对于慢性疼痛的发展或维持非常重要。