Trypsin mediates nociception via the proteinase-activated receptor 2: A potentially novel role in pancreatic pain
Trypsin mediates nociception via the proteinase-activated receptor 2: A potentially novel role in pancreatic pain
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DOI：
10.1053/j.gastro.2004.07.002
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发表时间：
2004-09-01
期刊：
影响因子：
29.4
通讯作者：
Pasricha, PJ
中科院分区：
文献类型：
--
作者：
Hoogerwerf, WA;Shenoy, M;Pasricha, PJ
背景与目的：胰腺炎疼痛的发病机制尚不清楚。我们推测在这种情况下的关键炎症介质胰蛋白酶也可以通过蛋白水解酶激活受体2激活伤害性神经元。方法：用抗蛋白酶激活受体2和香草素受体1的抗体对T8至T12背根神经节切片进行双重免疫组织化学染色。胰腺内注射蛋白酶激活的受体2激动剂后，用FOS免疫反应检测胸髓背角节段的伤害性活动。疼痛行为是通过内脏运动反射活性来评估的，这些反射活动是通过使用蛋白酶激活的受体2激动剂对胰腺的伤害性刺激做出反应的。结果：胸椎背根神经节几乎所有伤害性神经元均表达蛋白水解酶激活受体2。根据Fos表达的测量，导管内胰蛋白酶在亚炎症浓度下以剂量依赖的方式激活脊髓背角神经元。胰酶和一种蛋白酶激活的受体2特异性多肽激动剂在向清醒大鼠的胰管中注入时都会产生行为疼痛反应。胰管内预先注入蛋白酶激活受体2特异性激活肽可使胰酶反应减敏。结论：我们的研究结果表明，胰蛋白酶激活的受体2在胰腺疼痛的发病机制中发挥了一种新的作用，这种作用不依赖于其炎症效应。
Background & Aims: The pathogenesis of pain in pancreatitis remains poorly understood. We hypothesized that trypsin, a key inflammatory mediator in this condition, can also activate nociceptive neurons via the proteinase-activated receptor 2. Methods: Double immunohistochemical staining of T8 to T12 dorsal root ganglia sections was performed with antibodies against proteinase-activated receptor 2 and vanilloid receptor 1, a marker for primary nociceptive neurons. In vivo nociceptive activity was measured by FOS immunoreactivity in thoracic spinal dorsal horn segments after intrapancreatic administration of proteinase-activated receptor 2 agonists. Pain behavior was assessed by visceromotor reflex activity in response to noxious stimulation of the pancreas with proteinase-activated receptor 2 agonists. Results: Proteinase-activated receptor 2 was expressed by virtually all nociceptive neurons in thoracic dorsal root ganglia. Intraductal trypsin, in subinflammatory concentrations, activated spinal dorsal horn neurons in a dose-dependent manner, as measured by FOS expression. Both trypsin and a proteinase-activated receptor 2-specific peptide agonist induced a behavioral pain response when infused into the pancreatic duct of awake rats. Preinfusion of the pancreatic duct with proteinase-activated receptor 2-specific activating peptide desensitized the response to trypsin. Conclusions: Our findings suggest a novel proteinase-activated receptor 2-mediated role for trypsin in the pathogenesis of pancreatic pain and one that is independent of its inflammatory effect.