Chronic Compression of the Trigeminal Ganglia

描述(由申请人提供)：三叉神经痛(抽动)是一种异常疼痛的头面部疾病，其特征是面部剧烈刺痛，可由轻微触摸引起。在大多数病例中，疼痛可追溯到三叉神经根被血管慢性压迫，导致受压神经根脱髓鞘。这些压迫和髓鞘形成的变化可能会改变神经根上的Na+通道密度，可能导致异位放电和脉冲的纤维到纤维的异常传递。尽管一些钠离子通道阻滞剂在短期内有帮助，但许多患者最终接受了侵入性神经外科手术来减压神经根。然而，即使是手术，通常也只能提供暂时的缓解。限制新的、更有效的治疗方法开发的一个主要问题是缺乏准确模拟三叉神经痛的动物模型。RFA-DE-07-006“与三叉神经系统相关的新疼痛模型”的两个主要目标之一是“促进慢性口面部疼痛状况的新动物模型的开发和利用。作为这两个目标的补充，该计划还鼓励开发非侵入性和客观的、允许对疼痛进行行为或功能评估的患者和动物的新疼痛测量方法。”拟议研究的目标与这一目标非常吻合，因为我们计划开发一种准确的、可预测的三叉神经痛动物模型。我们的初步工作表明，经颅将生物相容的高吸水性聚合物放置在三叉神经根旁边，将三叉神经根推到骨骼上，提供了一种非炎性慢性压迫的手段，模拟了人类的病理。这项技术相对非侵入性，操作简单。此外，这些实验表明，这些动物表现出的行为和电生理变化与三叉神经痛的症状和体征高度一致。我们建议进一步描述这一模型，提供明确的终点来测试潜在的治疗方法，并提供一种检查三叉神经痛潜在机制的方法。这些机制研究反过来可以为药物开发和基因治疗方法确定新的靶点。

DESCRIPTION (provided by applicant): Trigeminal neuralgia (tic douloureux) is a devistatingly painful craniofacial disease, characterized by intense stabbing pains of the face which may be elicited by light touch. In the majority of cases, the pain can be traced to chronic compression of the trigeminal nerve roots by a blood vessel, leading to demyelination of the compressed roots. These compression and myelination changes may then alter Na+ channel density along the nerve root, possibly leading to ectopic discharges, and abnormal fiber-to-fiber transmission of impulses. Although some Na+ channel blocking anti-seizure drugs are helpful in the short-term, many patients end up having invasive neurosurgery to decompress the nerve root. Even surgery however, typically only provides temporary relief. A primary issue limiting the development of new, more effective therapies, has been the lack of an animal model which accurately simulates trigeminal neuralgia. One of the two main goals of RFA-DE-07-006 "New Models of Pain Relevant to the Trigeminal System" is to "stimulate the development and utilization of novel animal models of chronic orofacial pain conditions. As an adjunct to these two goals, this Initiative also encourages the development of novel measures of pain in patients and animals that are non-invasive and objective and that permit a behavioral or functional assessment of pain." The goal of the proposed research fits closely with this goal, in that we plan to develop an accurate, predictive animal model of trigeminal neuralgia. Our preliminary work has shown that transcranial placement of a biocompatible superabsorbant polymer next to the trigeminal nerve root pushes the root against the bone, providing a means of non-inflammatory chronic compression, simulating human pathology. The technique is relatively non-invasive and simple to perform. Furthermore, these experiments have shown that these animals demonstrate behavioral and electrophysiological changes that are highly consistent with the symptoms and signs of trigeminal neuralgia. We propose to further characterize this model, providing clear endpoints to test potential therapies and a means to examine mechanisms underlying trigeminal neuralgia. These mechanistic studies, in turn, can lead to the determination of new targets for pharmacdceutical development, as well as for gene therapy approaches.