TRANSLATIONAL MODEL FOR NOVEL THERAPEUTICS IN SPINAL CORD INJURY PAIN

描述(由申请人提供)：慢性疼痛是脊髓损伤(SCI)的一种经常使人虚弱且鲜为人知的后果。除了生活质量下降外，未经治疗的疼痛还会干扰充分参与康复策略的能力，从而减少在功能恢复方面潜在的长期收益。SCI疼痛是出了名的难以治疗，而且现有动物模型的复杂性阻碍了对有前景的药物治疗和新的干预策略的快速识别和筛选。这一针对PA-06-542(疼痛研究中的机制、模型、测量和管理)的探索性/开发性R21提案的目标是开发一个强大的预测模型，以简化这一过程，并促进有前景的疗法更快地转化为临床。我们实验室正在探索一种脊髓压迫损伤模型，该模型可以克服其他脊髓损伤疼痛模型的并发症，特别是对于损伤以下的神经病理性疼痛。初步研究结果显示，脊髓损伤疼痛症状强烈且持续可重现。因此，脊柱压迫模型提供了一个快速筛选公式的机会，用于评估临床相关止痛药和新疗法的效果。主要目标将是：1)利用一系列诱发和自发的结果测量，确定用于SCI疼痛快速筛查的挤压损伤模型的特征；2)利用已获批准并随时可用于临床的药物，开发包含这些行为结果的模型；3)利用该快速筛查模型来评估潜在的协同联合策略，并作为指导在慢性SCI疼痛的管理方面取得实质性改善。最初，将对临床批准的药理药物进行评估，因为它们在减少脊髓损伤疼痛方面可能具有尚未开发的潜在疗效，特别是在以选定的和协同的组合使用时，而且由于它们面临的监管障碍较少，可以更快地带到患者手中。由于患者经历了一系列症状，评估将包括机械性痛觉过敏、热痛觉过敏、冷过敏和持续性自发疼痛的测试(目标1)。将开发一个模型来选择有希望的药物，最初基于减少这些不同的神经性疼痛症状的有效性，并随着数据的收集而逐渐调整(目标2)。潜在的新的增效组合将利用等谱分析进行(目标3)。具有不同机制的药物的联合给药应该允许它们以显著较低的剂量给予，并减少不良反应，并可能导致单独使用次效或微效剂量的强效止痛。如果成功，这种方法的发展将迅速加快为患有慢性疼痛的脊髓损伤患者带来有效的止痛疗法的进程，包括新的干预策略。 项目简介：脊髓损伤后，许多患者遭受持续的疼痛，这可能是严重的和虚弱的，并限制了对康复计划的参与，导致更差的预后和功能恢复。对于脊髓损伤疼痛患者的药物选择是有限的，并且在当前的实践中略微有效，因此脊髓损伤疼痛是出了名的难以治疗。本研究的目的是开发和实施一种预测和有效的模型，用于快速筛选和翻译有前景的止痛疗法，以显著改善临床脊髓损伤疼痛的治疗。

DESCRIPTION (provided by applicant): Chronic pain is a frequently debilitating and poorly understood consequence of spinal cord injury (SCI). In addition to reduced quality of life, the presence of untreated pain can interfere with the ability to fully participate in rehabilitative strategies, thus reducing potential long-term gains in functional recovery. SCI pain is notoriously difficult to treat, and the complexities of available animal models impede the rapid identification and screening of promising pharmacotherapies and novel interventive strategies. The goal of this exploratory/developmental R21 proposal in response to PA-06-542 (Mechanisms, models, measurement, & management in pain research) is to develop a strong predictive model to streamline this process and facilitate translation of promising therapies more rapidly to the clinic. Our laboratory is exploring a spinal compression injury model which can overcome the complications of other SCI pain models, particularly for below-injury neuropathic pain. Preliminary findings demonstrate robust and persistent reproducible SCI pain symptoms. Thus, the spinal compression model offers an opportunity to generate a rapid screening formula for evaluating the effects of clinically relevant analgesic drugs and novel therapeutics. The primary objectives will be: 1) To characterize the compression injury model for use in rapid screening for SCI pain, using a battery of evoked and spontaneous outcome measures; 2) To develop a model incorporating these behavioral outcomes using agents that are already approved and readily available for clinical use; 3) To utilize this rapid screening model for evaluation of potentially synergistic combination strategies and serve as guidance for achieving substantial improvement in the management of chronic SCI pain. Initially, clinically approved pharmacologic agents will be evaluated, as they are likely to have untapped potential efficacy in reducing SCI pain, particularly when administered in selected and synergistic combinations and, since they face fewer regulatory hurdles, can be more rapidly brought to patients. Since patients experience a constellation of symptoms, evaluation will include tests for mechanical allodynia, heat hyperalgesia, cold hypersensitivity, and ongoing spontaneous pain (Aim 1). A model will be developed for selection of promising agents, based initially on efficacy in reducing these various neuropathic pain symptoms, and incrementally adjusted as data is collected (Aim 2). Potential novel synergistic combinations will be done using isobolographic analysis (Aim 3). The co-administration of agents with distinct mechanisms should allow them to be given in substantially lower doses with reduced untoward side effects, and can result in potent analgesia with subeffective or marginally effective doses of individual agents. If successful, the development of this approach should rapidly accelerate the process of bringing effective analgesic therapies, including novel interventive strategies, to SCI patients with chronic pain. Project Narrative: Following spinal cord injury, many patients suffer from long-lasting pain, which can be severe and debilitating, and limit participation in rehabilitation programs, resulting in poorer prognosis and reduced functional recovery. Pharmacological options for patients with SCI pain are limited and marginally effective in current practice, and thus SCI pain is notoriously difficult to treat. The goal of the proposed studies is to develop and implement a predictive and efficient model for rapidly screening and translating promising analgesic therapies to markedly improve the treatment of clinical spinal cord injury pain.