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: 7369672
• 负责人: SCOTT M. THOMPSON
• 金额: $ 16.24万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369672
• 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）：中枢性疼痛综合征（CPS）的特征是由脊髓、脑干或丘脑中的病变或病理引起的严重和难以忍受的疼痛，并且对任何治疗或药物都具有高度抗性。其原因尚不清楚。我的目标是建立一个啮齿动物模型的CPS，我们可以开始了解这种衰弱的条件下的细胞机制，并测试潜在的有用的治疗靶点，其治疗和/或预防。我推测，在大鼠或人类的脊髓中的上升感觉输入通路的病变导致部分去神经的中继细胞在丘脑的ventrobasal复合体，导致其兴奋性的延迟增加。这种过度兴奋性可能是由增加的内在神经元兴奋性（例如K+通道的下调或Ca 2+通道的上调）和/或增加的网络兴奋性（例如改变的突触抑制或兴奋）引起的。该假说预测，在失神癫痫中显示抗惊厥活性的药物，如乙琥胺，将降低丘脑过度兴奋性并缓解中枢疼痛综合征。我将测试这些假设，通过研究疼痛的感知与完善的行为范式，和丘脑神经元的内在和网络兴奋性在离体脑切片大鼠脊髓中的上行伤害性通路已被损坏。此外，我将测试乙琥胺和其他“丘脑”抗癫痫药物是否有效地恢复正常的疼痛感知并降低受伤大鼠脑片中丘脑神经元的兴奋性。这些实验应该增加我们对这种毁灭性疾病的起源的理解，并为急需的治疗缓解指明道路。我将尝试开发一种中枢性疼痛综合征的模型，这是一种头部或脊柱受伤的受害者所遭受的痛苦，在大鼠中，这样我们就可以了解这种使人衰弱的疾病的生物学原因，并提出治疗或预防它的新想法。