Mechanism of Neuropathic Pain (CRPS)

描述(申请人提供)：复杂性区域疼痛综合征(CRPS)是一个特别棘手的医学问题，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范例，这是本提案的长期目标。脊髓神经结扎模型是一种广泛使用的CRPS(II型伴主要神经损伤)大鼠模型，在本项资助的支持下，过去已对CRPS的外周机制的各个方面进行了研究。然而，在本赠款即将到来的资助期，重点将放在CRPS的脊髓机制上。总的假设是脊髓神经损伤导致脊髓内剧毒自由基--活性氧物种(ROS)水平持续升高，进而导致背角神经元的中枢敏化，这是CRPS的关键潜在机制。4)脊髓神经结扎导致脊髓ROS水平升高，2)ROS增加与中枢敏化和疼痛行为体征有关，3)ROS诱导的中枢敏化的一个重要机制是脊髓内GABA功能受损，4)随着时间的推移，许多背角神经元因长期暴露于ROS而死亡。目前的建议是使用多学科方法来检验这些假设。这些目标的成功完成不仅将揭示CRPS的重要脊髓机制，还可能导致以自由基清除剂为基础的新止痛药的开发。

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.