Mechanism of Neuropathic Pain (CRPS)

描述（由申请人提供）：复杂区域疼痛综合征（CRPS）是一个特别困难的医学问题，因为它是一种影响患者生活质量的慢性疾病，通常没有有效的治疗方法。因此，重要的是要了解CRPS的机制，从而允许开发新的治疗模式，这是该提案的长期目标。使用脊神经结扎模型，一种广泛使用的CRPS大鼠模型（II型主要神经损伤），CRPS的外周机制的各个方面已经在过去进行了研究，目前的资助支持。然而，在即将到来的资助期内，重点将放在CRPS的脊柱机制上。总体假设是，脊髓神经损伤诱导脊髓中高毒性自由基、活性氧（ROS）水平持续升高，进而导致背角神经元的中枢致敏，这是CRPS的关键潜在机制。提出了四个具体目标，以检验下列个别假设：1）脊神经结扎诱导脊髓ROS水平升高，2）增加的ROS与中枢敏化和疼痛的行为体征相关，3）ROS诱导的中枢敏化的重要机制是脊髓中GABA功能的损害，和4）随着时间的推移，许多背角神经元由于长期暴露于ROS而死亡。目前的建议是使用多学科的方法来测试这些假设。这些目标的成功实现不仅将揭示CRPS的重要脊髓机制，而且还可能导致基于自由基清除剂的新型镇痛药物的开发。

DESCRIPTION (provided by applicant): Complex regional pain syndrome (CRPS) is an especially difficult medical problem because it is a chronic disease affecting a patient's quality of life, often with no effective treatment. Therefore, it is important to understand the mechanisms of CRPS, thereby allowing new treatment paradigms to be developed, which is the long-term goal of this proposal. Using the spinal nerve ligation model, an extensively used rat model of CRPS (type II with major nerve injury), various aspects of the peripheral mechanisms of CRPS has been studied in the past, with support from the present grant. In the upcoming funding period of the present grant, however, the focus will be on spinal mechanisms of CRPS. The overall hypothesis is that spinal nerve injury induces a sustained elevated level of highly toxic free radicals, reactive oxygen species (ROS), in the spinal cord, leading in turn to central sensitization of dorsal horn neurons, which is the key underlying mechanism in CRPS. Four specific aims are proposed to test the following individual hypotheses: 1) that spinal nerve ligation induces an elevated level of spinal ROS, 2) that the increased ROS are associated with central sensitization and behavioral signs of pain, 3) that an important mechanism of ROS-induced central sensitization is impairment of GABA function in the cord, and 4) that as time passes many dorsal horn neurons die due to extended exposure to ROS. The present proposal is to test these hypotheses using a multidisciplinary approach. Successful completion of these aims will not only uncover important spinal mechanisms of CRPS but may also lead to the development of new analgesic drugs based on free radical scavengers.