Abnormal Dendritic Spines Underlie Neuropathic Pain and Spasticity in SCI

产品说明： 背景资料：我们的研究目的是确定一个临床上适用的治疗策略，顽固性疼痛和痉挛后脊髓损伤（SCI）。超过50%的患者 由于神经病理性疼痛和痉挛，SCI患者的生活质量严重下降，目前的药物治疗通常难以治愈。大约有42，000名美国退伍军人生活在SCI的身体和情感负担中，同时给整个社会带来经济负担。已知多种因素导致SCI后慢性疼痛和痉挛。树突棘是位于脑和脊髓中神经元分支上的微米级结构。由于树突棘在突触功能中起着不可或缺的作用，并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持功能提供了最佳的视觉线索。先前的工作已经证明SCI诱导的树突棘变化可以在CNS中产生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，靶向异常树突棘重塑代表了缓解SCI后神经病理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，脊髓损伤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，导致神经病理性疼痛和痉挛。为了解决这一假设，我们将研究SCI后树突棘重塑是否有助于神经病理性疼痛的发展和维持（目标1），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（NSC 23766）和基因治疗方法（即，显性阴性表达和Rac 1基因敲除）（目的3）。最后，在一个桥梁翻译研究（目标4），我们将在非人灵长类动物模型的SCI的树突棘形态。意义：该项目旨在直接使脊髓损伤患者受益。在超过250，000名患有严重脊髓损伤和疾病的美国人中，约有42，000人是美国退伍军人，他们有资格获得退伍军人事务部的医疗保健和其他福利。这些SCI患者中有50-80%经历临床上显著的疼痛和痉挛。尽管积极治疗，这些并发症是难治性的，目前的药物治疗。我们提出的工作将解决治疗脊髓损伤后神经病理性疼痛和痉挛的异常树突棘的潜在目标。我们的研究结果也将为未来翻译SCI患者疼痛和痉挛的治疗方法提供基础。

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.