癌症肿瘤学胰蛋酶蛋白酶活化受体2通路参与胰腺癌痛的发生维持.docVIP

胰蛋白酶-蛋白酶活化受体2通路参与胰腺癌痛的发生维持 Trypsin-PAR-2 pathway involved in the development and maintenance of pancreatic cancer pain 缪雪蓉，陆智杰，虞大为，朱海，邱海波，俞卫锋 作者单位：第二军医大学附属东方肝胆外科医院麻醉科，上海市长海路225号，200438； 本研究受到国家自然科学基金资助（项目号。 中文摘要： 目的：胰腺癌痛相当剧烈，有效控制胰腺癌痛成为临床上的迫切需要。本课题探讨胰蛋白酶-PAR-2通路在胰腺癌痛中的作用机制，以寻求新的镇痛靶点。方法：选取了临床有疼痛表现的胰腺癌患者病理标本，经过培养液孵育后取上清进行胰蛋白酶测定。并通过测定神经肽SP及CGRP的水平以及钙内流的变化，观察肿瘤组织孵育上清对培养的DRG神经元的激活作用。通过行为学方法评估大鼠足底注射孵育上清后的疼痛行为。最后，我们采用人胰腺癌细胞株SW1990建立了裸鼠原位胰腺癌痛模型，用行为评分以及内脏运动反射肌电图法评估疼痛行为。结果：胰腺癌组织比正常胰腺组织释放更多的胰蛋白酶。胰腺癌组织孵育上清可以激活外周感觉神经元，引起神经元SP和CGRP释放增多以及钙内流的增加。胰腺组织孵育上清足底注射后也可以引起大鼠的躯体伤害性感受行为，表现为行走跛足、机械性刺激和热辐射缩足阈值降低。胰蛋白酶的抑制剂FUT-175以及PAR-2特异性阻断肽FS-NH2则明显减轻了胰腺癌孵育上清引起的上述感觉神经元激活以及大鼠足底注射后的疼痛行为。在裸鼠原位胰腺癌痛模型上证实了PAR-2特异性阻断肽可以有效的缓解胰腺癌痛。结论：这些研究结果提示，胰腺癌组织释放的高水平的胰蛋白酶可以通过PAR-2受体激活感觉神经元，从而产生疼痛信号参与胰腺癌痛的发生维持；阻断PAR-2受体可以有效的缓解胰腺癌痛，这可能成为胰腺癌痛新的治疗靶点。 Background：Rapid and effective treatment of pancreatic cancer pain remains a clinical challenge. The protease activated receptor-2 (PAR-2) plays a critical role in many aspects of nociceptor function. Therefore, we investigated the potential role of trypsin-PAR-2 pathway in pancreatic cancer pain. Methods：Pancreatic carcinoma specimens and matched control samples were obtained from patients with pain who underwent surgery at Eastern Hepatobiliary Surgery Hospital. Supernatants from pancreatic carcinoma were used for activation of cultured DRG neurons and evocation of peripheral nociception behaviors in rats after intra-paw injection. Orthotopic implantation model of SW1990 cells in nude mice was used for determination of the role of trypsin-PAR-2 in pancreatic cancer pain. Results: Pancreatic carcinoma specimens from release increased levels of trypsin compared to normal controls. Specimens from pancreatic cancer patients (but not controls) released mediators that sensitized rat sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor FUT-175 and PAR-2 antagonist peptide. Specimens from pancreatic cancer patients, but not controls, al