明胶酶调制吗啡耐受与依赖形成的脊髓机制研究

项目名称： 明胶酶调制吗啡耐受与依赖形成的脊髓机制研究

项目编号： No.81200860

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 韩园

作者单位： 徐州医学院

项目金额： 23万元

中文摘要： 吗啡类药物的耐受性和成瘾性问题的发生机制一直是科研热点与难点，深入研究其发生机制并寻找新的干预靶点，提高吗啡的药效并减少副作用是迫切任务。明胶酶（MMP-2/9）是依赖于锌离子的内切蛋白水解酶，可通过裂解活化多种炎症因子、膜表面蛋白和细胞外蛋白，调控多种细胞功能与细胞间通信。申请者最新的研究首次表明：抑制脊髓水平MMP-9可有效抑制吗啡造成的脊髓中枢敏化和胶质细胞活化，显著缓解吗啡戒断的躯体症状，并增强吗啡镇痛效能。但是MMP-2/9在体内广泛存在，把其作为药物干预的直接靶点，副作用较大。深入研究明胶酶参与吗啡耐受和依赖形成的详细分子机制，可能找到新的药物干预靶点。本项目拟利用吗啡耐受和躯体依赖行为学模型，结合细胞和分子水平研究，阐明MMP-2/9调控脊髓不同细胞功能及细胞间通讯的详细分子机制。研究成果不仅有助于揭示吗啡耐受和依赖的形成机制，也为临床治疗提供新策略，为药物研发提供新靶标。

中文关键词： 明胶酶；吗啡耐受；神经炎症；突触可塑性；

英文摘要： The mechanisms of morphine tolerance and dependence remain elusive and continue to be the difficult issue of research. It is of clinical importance to find the specific mechanisms underlying opioid actions and develop medications to facilitate morphine utility. Gelatinase (MMP-2/9) are zinc dependent endopeptidases and can be detected in neuron and glia. Gelatinase can regulate diverse biological processes through cleavage of cytokines, cell surface receptors and extracellular proteins. The applicant has found that inhibition of spinal MMP-9 can suppresses neuron excitability, upregulation of molecular markers related to synaptic plasticity and the behavioral signs of naloxone-precipitated morphine withdrawal. Analgesic effects of morphine could also be rescued by inhibiting spinal MMP-9 or MMP-2. Those findings suggest that MMP-2/9 may play an important role in morphine tolerance and dependence. However, because MMP-2/9 widely express in CNS and play an important role in many physiological processes, there may be many bad side effects if they are taken as the therapeutic targets directly. Thus, we need to further investigate the roles of gelatinase in morphine dependence and tolerance, and find the new effective targets.We will use the behavior, western blotting, immunohistochemistry methods to investigate how

英文关键词： gelatinase；morphine tolerance；neuroninflammation；synaptic plasticity；