Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?

中枢性疼痛综合征：去神经后丘脑过度兴奋？

• 批准号: 7254559
• 负责人: SCOTT M. THOMPSON
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-05 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254559
• 关键词: Absence Epilepsy; Animals; Anticonvulsants; Antiepileptic Agents; Behavioral Assay; Behavioral Paradigm; Biological; Brain; Brain Stem; Cells; Complex; Condition; Deafferentation procedure; Dejerine Roussy Syndrome; Denervation; Down-Regulation; Ethosuximide; Fiber; Figs - dietary; Glutamates; Grant; Head; Human; Lesion; Measures; Modeling; Neurons; Nociception; Numbers; Output; Pain; Pathology; Pathway interactions; Perception; Pharmaceutical Preparations; Potassium Channel; Prevention; Rattus; Resistance; Rodent Model; Sensory; Slice; Spinal Cord; Spinal Injuries; Spinothalamic Tracts; Stimulus; Synapses; Syndrome; Testing; Thalamic structure; Therapeutic; Up-Regulation; Valproic Acid; central pain; injured; neuronal excitability; prevent; research study; response; synaptic inhibition; therapeutic target; voltage

DESCRIPTION (provided by applicant): Central Pain Syndrome (CPS) is characterized by severe and excruciating pain resulting from a lesion or pathology in the spinal cord, brainstem, or thalamus, and is highly resistant to any therapy or medication. Its cause is unknown. My objective is to develop a rodent model of CPS with which we can begin to understand the cellular mechanisms underlying this debilitating condition and test potentially useful therapeutic targets for its treatment and/or prevention. I hypothesize that a lesion of ascending sensory input pathways in the spinal cord of rats or humans causes partial denervation of relay cells in the ventrobasal complex of the thalamus resulting in a delayed increase in their excitability. This hyperexcitability might result from either increased intrinsic neuronal excitability (e.g. a downregulation of K+ channels or upregulation of Ca2+ channels) and/or increased network excitability (e.g. altered synaptic inhibition or excitation). The hypothesis predicts that drugs that display anticonvulsant activity in absence epilepsy, such as ethosuximde, will reduce excessive thalamic excitability and relieve central pain syndrome. I will test these hypotheses by investigating the perception of pain with well established behavioral paradigms, and the intrinsic and network excitability of thalamic neurons in ex vivo brain slices from rats in which ascending nociceptive pathways in the spinal cord have been lesioned. In addition, I will test whether ethosuximde and other 'thalamic' antiepileptic drugs effectively restore normal pain perception and decrease the excitability of thalamic neurons in brain slices from injured rats. These experiments should increase our understanding of the genesis of this devastating condition and point the way to sorely needed therapeutic relief. I will attempt to develop a model of Central Pain Syndrome, a form of excruciating pain suffered by victims of head or spinal injuries, in rats so that we can understand the biological causes of this debilitating condition and suggest new ideas for treating or preventing it.

描述（由申请人提供）：中央疼痛综合征（CPS）的特征是因脊髓，脑干或丘脑病变或病理而导致的严重和令人难以置信的疼痛，并且对任何疗法或药物都有高度抗性。它的原因是未知的。我的目标是开发CP的啮齿动物模型，我们可以开始了解这种使人衰弱状况的细胞机制，并测试其治疗和/或预防的潜在有用的治疗靶标。我假设在大鼠或人类的脊髓上升高的感觉输入途径的病变会导致丘脑腹侧复合物中继电器细胞的部分神经化，从而导致其兴奋性延迟。这种过度刺激性可能是由于内在神经元兴奋性增加（例如，K+通道的下调或CA2+通道的上调）和/或网络兴奋性增加（例如突触抑制或激发改变）。该假设预测，在缺席癫痫的情况下显示抗惊厥活性的药物（例如Ethosuximde）将降低过度的丘脑兴奋性并缓解中枢性疼痛综合征。我将通过研究以良好的行为范式的疼痛感知来检验这些假设，以及从大鼠的tenamic神经元中丘脑神经元在脊柱中升高的伤害感受途径的内在和网络兴奋性。此外，我还将测试Ethosuximde和其他“丘脑”抗癫痫药是否有效地恢复了正常的疼痛感，并降低了受伤大鼠脑切片中丘脑神经元的兴奋性。这些实验应增加我们对这种毁灭性状况的起源的理解，并指向迫切需要治疗的方法。我将尝试开发一种中央疼痛综合征模型，这是大鼠头部或脊柱损伤受害者所遭受的一种令人发指的疼痛形式，以便我们可以理解这种令人衰弱的疾病的生物学原因，并提出了治疗或预防疾病的新想法。