Sciatic ligation, spinal plasticity and neuropathic pain

坐骨结扎、脊柱可塑性和神经性疼痛

• 批准号: 7749997
• 负责人: GORDANA MILETIC
• 金额: $ 25.47万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749997
• 关键词: Acute Pain; Affect; Affinity; Animals; Attenuated; Behavioral; Biological; Brain; Brain-Derived Neurotrophic Factor; Chemosensitization; Communication; Data; Development; Disease; Down-Regulation; Dyes; Equilibrium; Esthesia; Event; Exhibits; Fiber; Future; Gene Expression; Genes; Goals; Health; Healthcare; Heating; Hour; Immunofluorescence Immunologic; Injury; Ipsilateral; Label; Learning; Ligation; Mechanics; Mediating; Memory; Messenger RNA; Modeling; Monitor; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear Protein; Nuclear Proteins; Pain; Peripheral nerve injury; Persistent pain; Phase; Phosphorylation; Posterior Horn Cells; Potassium Chloride; Process; Productivity; Protein Tyrosine Kinase; Proteins; Quality of life; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Specificity; Spinal; Testing; Therapeutic; Therapeutic Intervention; Ursidae Family; Weight-Bearing state; Western Blotting; Withdrawal; behavior test; cost; dorsal horn; gamma-Aminobutyric Acid; immunoreactivity; neuronal excitability; neurotrophic factor; pain behavior; painful neuropathy; prevent; programs; protein expression; receptor; research study; response; sciatic nerve; symporter

Activity-dependent plasticity in the spinal dorsal horn may at least partly underlie the development of neuropathic pain following peripheral nerve injury. This form of plasticity allows for enhanced neuronal communication, and in the brain, it may enable learning and memory. However, in the spinal dorsal horn it may transform the essential but rapidly terminated sensation of acute pain into unproductive persistent pain. In this application we propose to employ the well-established loose ligation of the sciatic nerve model of neuropathic pain, and investigate the potential interaction between brain derived neurotrophic factor (BDNF) and the potassium-chloride co-transporter 2 (KCC2) in the early phase of injury-elicited spinal plasticity,i.e., in the first few hours after sciatic ligation. Our central hypothesis is that BDNF-mediated down-regulation of KCC2 promotes an early increase in dorsal horn neuronal excitability. We surmise that this increase in excitability contributes significantly to the initial development of spinal plasticity and to the ensuing early behavioral signs of neuropathic pain. In Specific Aim 1 we will examine the early consequences of sciatic ligation on KCC2 gene expression and protein levels in the dorsal horn, and establish if changes in KCC2 levels are dependent on the activation of the high-affinity BDNF TrkB receptors. In Specific Aim 2 we will functionally assess the early consequences of sciatic ligation or local BDNF application on neuronal excitability, and we will determine if a block of TrkB receptors or KCC2 activity modifies this excitability. In Specific Aim 3 we will establish the behavioral relevance of the pharmacological manipulation of TrkB receptors or KCC2 activity on the early expression of neuropathic pain. Neuropathic pain is a serious health problem with profound effects on the quality of life. It is a debilitating disease that affects millions of people and costs billions of dollars in health care and lost productivity. Through a detailed examination of the interplay between BDNF and KCC2 we hope to achieve two goals. First, from a purely biological perspective we wish to delineate the early consequences of peripheral nerve injury on dorsal horn neuronal activity. Second, from a therapeutic perspective, we seek to achieve better target specificity for more effective future therapeutic interventions.

脊髓背角的活动依赖性可塑性可能至少部分地是 周围神经损伤后的神经性疼痛。这种形式的可塑性允许增强神经元 在大脑中，它可以使学习和记忆。然而，在脊髓背角， 可将急性疼痛的基本但迅速终止的感觉转变为无效的持续性疼痛。 在本申请中，我们提出采用成熟的坐骨神经松结扎模型， 神经病理性疼痛，并探讨脑源性神经营养因子（BDNF） 和氯化钾协同转运蛋白2（KCC2）在损伤引起的脊髓可塑性的早期阶段，即， 在坐骨神经结扎后的最初几个小时内。我们的中心假设是，BDNF介导的下调 KCC 2促进背角神经元兴奋性的早期增加。我们认为，这种增长 兴奋性对脊髓可塑性的最初发育和随后的早期发育有重要作用。 神经性疼痛的行为体征。 在具体目标1中，我们将研究坐骨神经结扎对KCC2基因表达的早期影响。 以及背角中的蛋白质水平，并确定KCC2水平的变化是否依赖于 高亲和力BDNF TrkB受体的激活。在具体目标2中，我们将对早期 坐骨神经结扎或局部BDNF应用对神经元兴奋性的影响，我们将确定 TrkB受体或KCC2活性的阻断改变了这种兴奋性。在具体目标3中，我们将建立 TrkB受体或KCC2活性的药理学操作对早期 神经病理性疼痛的表达。 神经病理性疼痛是一种严重的健康问题，对生活质量有着深远的影响。这是一个削弱 这种疾病影响数百万人，花费数十亿美元的医疗保健和生产力损失。 通过详细研究BDNF和KCC2之间的相互作用，我们希望实现两个目标。 首先，从纯生物学的角度来看，我们希望描绘周围神经损伤的早期后果。 脊髓背角神经元活动损伤。第二，从治疗的角度来看，我们寻求更好地实现 靶向特异性，以便将来进行更有效的治疗干预。