Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?

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耐药性。其原因尚不清楚。我的目标是建立一个啮齿动物CPS模型，通过这个模型，我们可以开始了解这种使人衰弱的疾病的细胞机制，并测试治疗和/或预防它的潜在有用的治疗靶点。我假设，大鼠或人类脊髓上行感觉输入通路的损伤导致丘脑腹底复合体中继细胞的部分失神经支配，从而导致其兴奋性的延迟增加。这种高兴奋性可能是由于神经元固有兴奋性增加（如K+通道下调或Ca2+通道上调）和/或网络兴奋性增加（如突触抑制或兴奋改变）。该假说预测，在缺乏性癫痫中表现出抗惊厥活性的药物，如乙thosuximde，将减少丘脑的过度兴奋性，缓解中枢疼痛综合征。我将对这些假设进行验证，方法是研究具有良好行为模式的疼痛感知，以及在脊髓上行伤害性通路受损的大鼠离体脑切片中丘脑神经元的内在和网络兴奋性。此外，我将测试乙索辛胺和其他“丘脑”抗癫痫药物是否能有效地恢复损伤大鼠的正常痛觉，并降低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，并为迫切需要的治疗缓解指明道路。我将尝试建立一个中枢性疼痛综合征的模型，这是一种由头部或脊柱受伤的受害者遭受的剧痛，在老鼠身上，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。

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.