Abnormal Dendritic Spines Underlie Neuropathic Pain and Spasticity in SCI

异常树突棘是 SCI 中神经病理性疼痛和痉挛的基础

• 批准号: 9207355
• 负责人: Andrew Michael Tan
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207355
• 关键词: Acute; Address; American; Attenuated; Autopsy; Behavior; Biological Neural Networks; Brain; Caring; Chemosensitization; Chronic; Data; Dendritic Spines; Development; Disease; Dominant-Negative Mutation; Dysplasia; Early treatment; Economic Burden; Eligibility Determination; Emotional; Foundations; Functional disorder; Future; Genes; Goals; Individual; Injury; Intervention; Intractable Pain; Investigation; Knowledge; Maintenance; Mediating; Medical; Mentors; Modeling; Morphology; Motor; Motor Neurons; Neurons; Nociception; Pain; Pain management; Patients; Pharmacology; Play; Quality of life; Reflex action; Reflex control; Refractory; Relapse; Research; Role; Sensory; Signal Transduction; Site; Societies; Spastic; Spinal; Spinal Cord; Spinal cord injury; Structure; Synapses; System; Therapeutic; Tissues; Translations; Treatment Efficacy; Ventral Horn of the Spinal Cord; Vertebral column; Veterans; Viral; Visual; Work; attenuation; chronic pain; clinical application; clinical translation; clinically significant; experience; gene therapy; inhibitor/antagonist; knock-down; motor neuron development; nonhuman primate; pain symptom; painful neuropathy; preclinical study; prevent; public health relevance; sensorimotor system; spasticity; spinal reflex; synaptic function; targeted treatment; translational study; treatment strategy

DESCRIPTION: Background: The goal of our research is to identify a clinically applicable treatment strategy for intractable pain and spasticity after spinal cord injury (SCI). Over fifty percent of patients with SCI live a severely diminished quality of life due to neuropathic pain and spasticity that are ofte refractory to current medical treatments.There are approximately 42,000 US Veterans living with the physical and emotional burden of SCI while posing an economic burden to society at large. A variety of factors are known to contribute to chronic pain and spasticity after SCI. Dendritic spines are micron-sized structures located on neuronal branches in the brain and spinal cord. Because dendritic spines play an integral role in synaptic function and represent modifiable sites of synaptic contact, they provide the best visual clue into how neural networks form and retain function. Previous work has demonstrated that SCI-induced dendritic spine changes can produce long-lasting potentiation of nociceptive signals in the CNS, resulting in neuropathic pain, and contribute to the increased excitability of spinal reflex control associated with spasticity. Thus, targeting aberrant dendritic spine remodeling represents a potentially effective therapeutic approach for alleviating neuropathic pain and spasticity after SCI. Research Plan: Our main hypothesis is that dendritic spine remodeling after SCI contributes to the maintenance of hyperexcitability in spinal sensory and motor systems, leading to neuropathic pain and spasticity. To address this hypothesis, we will investigate whether dendritic spine remodeling after SCI contributes to the development and maintenance of neuropathic pain (Objective 1), and to dysfunction of the spinal motor reflex system (Objective 2). We will also determine the contribution of abnormal dendritic spine remodeling on spinal motor neurons to spinal reflex dysfunction and spasticity after SCI through the utilization of both a pharmacological approach (NSC23766) and a gene therapy approach (i.e., dominant-negative expression and Rac1 gene knockdown) (Objective 3). Finally, in a bridge-to-translation study (Objective 4), we will profile dendritic spine morphology in a non-human primate model of SCI. Significance: This project aims to directly benefit those with spinal cord injury. Of the >250,000 Americans with serious spinal cord injuries and disorders, about 42,000 are U.S. Veterans who are eligible for medical care and other benefits from the Department of Veterans Affairs. 50-80% of these individuals with SCI experience clinically significant pain and spasticity. Despite aggressive treatment, these complications are refractory to current medical treatments. Our proposed work will address the therapeutic potential targeting of abnormal dendritic spines in neuropathic pain and spasticity after SCI. Our findings will also provide the foundation for future translation of therapeutic treatment for pain and spasticity in patients with SCI.

描述： 背景：我们研究的目的是确定一种临床适用的治疗脊髓损伤（SCI）后顽固性疼痛和痉挛的策略。百分之五十以上的患者 由于神经性疼痛和痉挛，目前的药物治疗往往难以治愈，SCI 导致生活质量严重下降。大约有 42,000 名美国退伍军人承受着 SCI 的身体和情感负担，同时给整个社会带来了经济负担。已知多种因素会导致 SCI 后的慢性疼痛和痉挛。树突棘是位于大脑和脊髓神经元分支上的微米大小的结构。由于树突棘在突触功能中发挥着不可或缺的作用，并且代表了突触接触的可修改位点，因此它们为神经网络如何形成和保留功能提供了最佳的视觉线索。先前的研究表明，SCI 引起的树突棘变化可以产生中枢神经系统中伤害性信号的持久增强，导致神经性疼痛，并有助于增加与痉挛相关的脊髓反射控制的兴奋性。因此，针对异常树突棘重塑是缓解 SCI 后神经性疼痛和痉挛的潜在有效治疗方法。研究计划：我们的主要假设是，SCI 后树突棘重塑有助于维持脊髓感觉和运动系统的过度兴奋，导致神经性疼痛和痉挛。为了解决这一假设，我们将研究 SCI 后的树突棘重塑是否会导致神经性疼痛（目标 1）的发生和维持，以及脊髓运动反射系统的功能障碍（目标 2）。我们还将通过利用药理学方法 (NSC23766) 和基因治疗方法（即显性失活表达和 Rac1 基因敲低）确定脊髓运动神经元异常树突棘重塑对 SCI 后脊髓反射功能障碍和痉挛的影响）（目标 3）。最后，在翻译桥梁研究（目标 4）中，我们将在非人类灵长类 SCI 模型中描绘树突棘形态。意义：该项目旨在直接造福脊髓损伤患者。在超过 250,000 名患有严重脊髓损伤和疾病的美国人中，约 42,000 人是美国退伍军人，他们有资格享受退伍军人事务部的医疗护理和其他福利。 50-80% 的 SCI 患者会经历临床上明显的疼痛和痉挛。尽管进行了积极的治疗，但目前的药物治疗仍难以治愈这些并发症。我们提出的工作将解决 SCI 后神经性疼痛和痉挛中异常树突棘的治疗潜力。我们的研究结果还将为未来 SCI 患者疼痛和痉挛治疗的转化奠定基础。