The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents
The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents
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DOI：
10.1016/j.lfs.2007.02.044
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发表时间：
2007-05-01
期刊：
影响因子：
6.1
通讯作者：
Kawabata, Atsufumi
中科院分区：
文献类型：
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作者：
Ishikura, Hiroyasu;Nishimura, Sachiyo;Kawabata, Atsufumi
甲磺酸卡莫他是一种口服的蛋白酶抑制剂，临床上用于治疗胰腺炎。鉴于最近的证据表明胰腺蛋白酶包括胰蛋白酶和/或蛋白酶活化受体-2 （PAR2）可能参与胰腺疼痛，我们研究了甲磺酸卡莫司他是否可以抑制脊髓Fos的表达，这是神经元激活的标志，在胰蛋白酶特异性应用于胰腺和胰腺炎相关的异常性疼痛后。胰酶注入胰管后，大鼠双侧T8和T9脊髓背角浅层Fos蛋白表达延迟。口服甲磺酸卡莫他300 mg/kg可完全消除胰蛋白酶诱导的脊髓Fos表达。每小时重复（共6次）给药后，小鼠表现出典型的胰腺炎症状，并伴有上腹部机械性异常痛（即，参考痛觉过敏/异常痛），通过使用von Frey纤维进行评估。甲磺酸卡莫他100 ~ 300 mg/kg，在第1次和第4次给药前口服2次，可消除胰腺炎相关性腹部异常性疼痛，部分预防炎症征象。同样剂量的甲磺酸卡莫他，在末次给药后给药一次，也显示出显著的抗异动作用。这些数据表明，甲磺酸卡莫司他可以预防和/或抑制胰腺炎引起的疼痛和/或牵涉性痛觉过敏/异常性疼痛，其中蛋白酶包括胰蛋白酶将发挥关键作用。(C) 2007爱思唯尔公司版权所有。
Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral preadministration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100-300 mg/kg, given orally twice before the 1st and 4th doses of cacrulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role. (C) 2007 Elsevier Inc. All rights reserved.