Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway.
Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway.
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DOI：
10.1016/j.pain.2010.02.010
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发表时间：
2010-05
期刊：
影响因子：
7.4
通讯作者：
Schmidt BL
中科院分区：
文献类型：
--
作者：
Lam DK;Schmidt BL
参与癌症患者疼痛产生的介质知之甚少。使用组合的分子，药理学，行为学和遗传学的方法，我们已经确定了蛋白酶激活受体2（PAR 2）诱导的癌症依赖性异常性疼痛的新机制。在这里，我们表明，人类头颈癌细胞的蛋白水解活性水平增加相比，正常的人类细胞控制。人癌细胞的上清液，而不是对照，造成明显的和长期的机械异常性疼痛的小鼠，当给药到后爪。这种伤害性作用被丝氨酸蛋白酶抑制剂消除，肥大细胞耗竭减少，PAR 2缺陷小鼠中不存在。此外，三叉神经节神经元与人头颈癌细胞的非接触共培养增加了表现出PAR 2免疫反应性的神经元的比例。我们的研究结果指出丝氨酸蛋白酶及其受体在癌痛发病机制中的直接作用。这种以前未被认识到的癌症疼痛途径具有重要的治疗意义，其中丝氨酸蛋白酶抑制剂和PAR 2拮抗剂可用于治疗癌症疼痛。
Mediators involved in the generation of pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell-depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer pain. This previously unrecognized cancer pain pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer pain.
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影响因子：
29.4
作者：
Hoogerwerf, WA;Shenoy, M;Pasricha, PJ
通讯作者：
Pasricha, PJ
影响因子：
6.1
作者：
Ishikura, Hiroyasu;Nishimura, Sachiyo;Kawabata, Atsufumi
通讯作者：
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DOI：
10.1124/jpet.103.061291
发表时间：
2004-04-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
4
作者：
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通讯作者：
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影响因子：
5.5
作者：
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通讯作者：
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