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）的一种经常使人衰弱且鲜为人知的后果。除了降低生活质量外，未经治疗的疼痛还会干扰患者充分参与康复策略的能力，从而降低功能恢复的潜在长期收益。众所周知，脊髓损伤疼痛难以治疗，现有动物模型的复杂性阻碍了快速识别和筛选有希望的药物治疗和新的干预策略。为了响应PA-06-542（疼痛研究中的机制、模型、测量和管理），本探索性/发展性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，并促进有希望的治疗方法更快地转化为临床。我们的实验室正在探索一种脊柱压迫损伤模型，它可以克服其他脊髓损伤模型的并发症，特别是损伤下神经性疼痛。初步研究结果显示，脊髓损伤疼痛症状强劲且持续可重复。因此，脊髓压迫模型提供了一个快速筛选公式，用于评估临床相关镇痛药物和新疗法的效果。主要目标将是：1)利用一系列诱发和自发结果测量来表征用于快速筛选SCI疼痛的压迫损伤模型；2)开发一个模型，使用已经批准并易于临床使用的药物，将这些行为结果纳入其中；3)利用该快速筛选模型评估潜在的协同联合策略，为实现慢性SCI疼痛管理的实质性改善提供指导。最初，将对临床批准的药物进行评估，因为它们可能在减轻脊髓损伤疼痛方面具有尚未开发的潜在功效，特别是在选择和协同联合使用时，因为它们面临的监管障碍较少，可以更快地带给患者。由于患者经历一系列症状，评估将包括机械异常性痛、热痛觉过敏、冷过敏和持续自发性疼痛的测试（目的1）。将建立一个模型来选择有希望的药物，最初基于减轻各种神经性疼痛症状的疗效，并随着数据的收集而逐渐调整（目标2）。潜在的新型协同组合将使用等容积分析进行（目标3）。具有不同作用机制的药物的联合给药应使它们以较低的剂量给予，减少不良副作用，并且可以在单个药物的次有效或边际有效剂量下产生强效镇痛。如果成功，这种方法的发展将迅速加速为慢性疼痛的脊髓损伤患者带来有效的镇痛疗法的进程，包括新的干预策略。

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.