Crucial role of neutrophils in the development of mechanical inflammatory hypernociception
Crucial role of neutrophils in the development of mechanical inflammatory hypernociception
复制标题
DOI：
10.1189/jlb.0907654
复制
发表时间：
2008-04-01
影响因子：
5.5
通讯作者：
Cunha, Fernando Q.
中科院分区：
文献类型：
--
作者：
Cunha, Thiago M.;Verri, Waldiceu A., Jr.;Cunha, Fernando Q.
神经元迁移是炎性疾病中观察到的组织损伤的原因。中性粒细胞也参与炎症性伤害感受，但其参与机制尚未阐明。在本研究中，我们解决了角叉菜胶诱导的机械痛觉过敏，这是确定使用修改的Randall-Sellito测试在大鼠中的这些机制。通过测定髓过氧化物酶活性来确定神经元在足底组织中的积聚，而细胞因子和PGE（2）水平分别用ELISA和放射免疫法测定。用岩藻多糖（一种白细胞粘附抑制剂）预处理大鼠，对角叉菜胶诱导的高伤害性感受具有剂量和时间依赖性。岩藻多糖对高伤害感受的抑制与防止中性粒细胞募集有关，因为它不能抑制由直接作用的高伤害感受介质PGE（2）和多巴胺诱导的高伤害感受，这两种介质引起高伤害感受，不依赖于中性粒细胞。岩藻多糖对角叉菜胶诱导的TNF-α、IL-1 β和姜黄素诱导的中性粒细胞趋化因子1（CINC-1）/CXCL 1的产生没有影响，表明中性粒细胞不是高伤害性细胞因子的来源。相反，由TNF-α、IL-1 β和CINC-1/CXCL 1诱导的高度伤害感受和中性粒细胞迁移被岩藻多糖抑制，表明中性粒细胞参与了直接作用的高度伤害感受介质的产生。事实上，在体外用IL-1 β刺激中性粒细胞产生PGE（2），而在大鼠爪中IL-1 β诱导的PGE（2）的产生被岩藻多糖预处理抑制。总之，在炎症过程中，迁移的中性粒细胞参与了导致机械性痛觉过敏的级联反应，至少通过介导直接作用的痛觉过敏介质（如PGE）的释放（2）。因此，阻断中性粒细胞迁移可能是开发新的镇痛药物的靶点。
Neutrophil migration is responsible for tissue damage observed in inflammatory diseases. Neutrophils are also implicated in inflammatory nociception, but mechanisms of their participation have not been elucidated. In the present study, we addressed these mechanisms in the carrageenan-induced mechanical hypernociception, which was determined using a modification of the Randall-Sellito test in rats. Neutrophil accumulation into the plantar tissue was determined by the contents of myeloperoxidase activity, whereas cytokines and PGE(2) levels were measured by ELISA and radioimmunoassay, respectively. The pretreatment of rats with fucoidin (a leukocyte adhesion inhibitor) inhibited carrageenan-induced hypernociception in a dose- and time-dependent manner. Inhibition of hypernociception by fucoidin was associated with prevention of neutrophil recruitment, as it did not inhibit the hypernociception induced by the direct-acting hypernociceptive mediators, PGE(2) and dopamine, which cause hypernociception, independent of neutrophils. Fucoidin had no effect on carrageenan-induced TNF-alpha, IL-1 beta, and cytokine-induced neutrophil chemoattractant 1 (CINC-1)/CXCL1 production, suggesting that neutrophils were not the source of hypernociceptive cytokines. Conversely, hypernociception and neutrophil migration induced by TNF-alpha, IL-1 beta, and CINC-1/CXCL1 was inhibited by fucoidin, suggesting that neutrophils are involved in the production of direct-acting hypernociceptive mediators. Indeed, neutrophils stimulated in vitro with IL-1 beta produced PGE(2), and IL-1 beta-induced PGE(2) production in the rat paw was inhibited by the pretreatment with fucoidin. In conclusion, during the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, at least by mediating the release of direct-acting hypernociceptive mediators, such as PGE(2). Therefore, the blockade of neutrophil migration could be a target to development of new analgesic drugs.