Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a
Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a
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DOI：
10.1016/s1526-5900(03)00636-9
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发表时间：
2003-08-01
期刊：
影响因子：
4
通讯作者：
Pasricha, PJ
中科院分区：
文献类型：
--
作者：
Winston, JH;Toma, H;Pasricha, PJ
虽然疼痛是胰腺炎的主要特征，但其发病机制知之甚少，治疗仍然困难。在几种躯体疼痛模型中，伤害性敏化与蛋白激酶的激活有关，包括trkA、蛋白激酶C和蛋白激酶A。因此，我们测试的假设，全身治疗激酶抑制剂，k252 a，已知抑制所有这些激酶将减轻疼痛的胰腺炎动物模型。在L-精氨酸诱导的急性坏死性胰腺炎大鼠模型中，评价了躯体参考区的Von Frey细丝测试作为测量参考痛的方法。胰腺炎大鼠表现出对Von Frey细丝腹部刺激的敏感性增加。这种机械敏感性与胰腺中磷酸化trkA水平增加8倍、胸背根神经节中降钙素基因相关肽和前速激肽原mRNA表达显著上调以及脊髓T10段中降钙素基因相关肽和P物质免疫反应性增加相关。用激酶抑制剂k252 a治疗抑制了胰腺中trkA的磷酸化，并逆转了与胰腺炎相关的行为变化和神经肽表达增加。(C)2003年，美国疼痛协会。
Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immuncireactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis. (C) 2003 by the American Pain Society.