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脊髓损伤（SCI）后的临床适用治疗策略（SCI）。超过50％的患者 SCI由于神经性疼痛和痉挛而导致的生活质量严重降低，这对当前的医疗治疗感到难治。大约有42,000名美国退伍军人生活在SCI的身体和情感上，同时给社会带来了经济负担。已知多种因素会导致SCI后慢性疼痛和痉挛。树突状刺是位于大脑和脊髓神经元分支上的微米大小结构。由于树突状刺在突触功能中起着不可或缺的作用，并表示突触接触的可修改位点，因此它们为神经网络形成和保留功能提供了最佳的视觉线索。先前的工作表明，SCI诱导的树突状脊柱变化可以在中枢神经系统中产生持久的伤害性信号的增强，从而导致神经性疼痛，并有助于增加与痉挛相关的脊柱反射对照的兴奋性。因此，靶向异常的树突状脊柱重塑代表了一种缓解SCI后神经性疼痛和痉挛性的潜在有效治疗方法。研究计划：我们的主要假设是SCI后的树突状脊柱重塑有助于维持脊柱感觉和运动系统中的过度兴奋性，从而导致神经性疼痛和痉挛。为了解决这一假设，我们将研究SCI后的树突状脊柱重塑是否有助于神经性疼痛的发展和维持（目标1）以及脊柱运动反射系统的功能障碍（目标2）。我们还将通过使用药理学方法（NSC23766）（NSC23766）和一种基因治疗方法（即主导 - 维持的表达和RAC1 Gene optign optiaral-negation-nocation-nocation-nocation-nocation-nocation and Race optign offects optiaral-nocation-nocation and Race optightown）（IMPLATEN）（OPPRECTING OPTICEND）（客观3）（客观3）（客观3），通过利用SCI后的脊柱反射功能障碍和痉挛性异常对脊柱反射功能障碍和痉挛的贡献。最后，在一项桥梁到翻译研究中（目标4），我们将在非人类灵长类动物模型中介绍树突状的脊柱形态。意义：该项目旨在直接使脊髓损伤的人受益。在严重的脊髓损伤和疾病严重的美国人中，约有42,000名有资格获得医疗保健的美国退伍军人，并从退伍军人事务部受益。这些患有SCI的人中有50-80％经历了临床上显着的疼痛和痉挛。尽管进行了积极的治疗，但这些并发症对当前的药物治疗仍然是难治性的。我们提出的工作将解决SCI后神经性疼痛和痉挛中树突状刺异常的治疗潜力靶向。我们的发现还将为SCI患者的疼痛和痉挛治疗的将来翻译提供基础。