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）的一种常见的使人衰弱且知之甚少的后果。除了降低生活质量外，未经治疗的疼痛可能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，SCI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前途的药物治疗和新的干预策略。根据PA-06-542（疼痛研究中的机制、模型、测量和管理），本探索性/开发性R21提案的目标是开发一个强有力的预测模型，以简化该过程，并促进将有前景的疗法更快地转化为临床。我们的实验室正在探索一种可以克服其他SCI疼痛模型的并发症的脊髓压迫损伤模型，特别是对于损伤下的神经性疼痛。初步研究结果表明，脊髓损伤疼痛症状是稳定和持续的。因此，脊柱压缩模型提供了一个机会，以产生一个快速筛选公式，用于评估临床相关的镇痛药物和新的治疗效果。主要目标是：1）使用一系列诱发和自发结果测量来表征用于快速筛查SCI疼痛的压迫损伤模型; 2）使用已经批准并易于临床使用的试剂来开发包含这些行为结果的模型; 3）利用这种快速筛选模型来评估潜在的协同组合策略，并作为实现慢性SCI疼痛管理的实质性改善的指导。最初，将对临床批准的药理学药物进行评估，因为它们可能在减轻SCI疼痛方面具有尚未开发的潜在疗效，特别是当以选定的协同组合给药时，并且由于它们面临的监管障碍较少，可以更快地带给患者。由于患者出现一系列症状，因此评价将包括机械性异常性疼痛、热痛觉过敏、冷超敏反应和持续自发性疼痛（目的1）。将开发用于选择有前景的药物的模型，最初基于减轻这些各种神经性疼痛症状的功效，并随着数据的收集而逐步调整（目标2）。潜在的新型协同组合将使用等效线分析进行（目标3）。具有不同机制的药物的共同给药应允许它们以显著较低的剂量给予，同时减少不良副作用，并且可以导致具有亚有效或边缘有效剂量的单个药物的强效镇痛。如果成功的话，这种方法的发展将迅速加速为患有慢性疼痛的SCI患者提供有效的镇痛治疗，包括新的干预策略。 项目叙述：脊髓损伤后，许多患者遭受长期的疼痛，这可能是严重的和衰弱的，并限制参与康复计划，导致预后较差和功能恢复减少。SCI疼痛患者的药理学选择是有限的，在目前的实践中，边际有效，因此SCI疼痛是出了名的难以治疗。拟议的研究的目标是开发和实施一个预测和有效的模型，快速筛选和翻译有前途的镇痛治疗，以显着提高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.