Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons
Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons
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DOI：
10.1016/j.pain.2003.12.034
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发表时间：
2004-04-01
期刊：
影响因子：
7.4
通讯作者：
Noguchi, K
中科院分区：
文献类型：
--
作者：
Dai, Y;Fukuoka, T;Noguchi, K
炎症中机械性痛觉过敏的机制可能涉及一种“机械化学”过程，即拉伸引起受损组织释放5'-三磷酸腺苷（ATP），然后刺激附近的初级感觉神经末梢。在本研究中，磷酸化的细胞外信号调节蛋白激酶（pERK）免疫反应性被用作指示初级传入神经元功能激活的标志物，以检测大鼠外周炎症模型中P2X受体介导的DRG神经元的有害反应。我们发现，在正常大鼠足底注射α， β亚甲基atp （alphaBme-ATP）后，很少检测到perk标记的DRG神经元。然而，将α - atp注射到完全弗氏佐剂（CFA）诱导的炎症足后，许多DRG神经元被标记为pERK。73%的perk标记DRG神经元共表达P2X3受体。在对cfa炎症大鼠后爪进行机械有害刺激后，我们发现与正常大鼠相比，有更多的perk标记神经元。P2X3受体拮抗剂吡哆醛磷酸-6-偶氮苯基-2′，4′-二磺酸或2′-（或3）- o -（三硝基苯）腺苷5′-三磷酸（TNP-ATP）可显著降低cfa炎症大鼠机械刺激诱发的pERK标记，但正常大鼠无此作用。我们还发现，在cfa炎症大鼠中，有髓鞘的A纤维被标记为pERK的神经元募集，这被P2X3受体拮抗剂逆转。此外，tnf - atp剂量依赖性地降低了CFA大鼠的机械超敏反应。这些数据表明，初级传入神经元中的P2X受体在炎症期间随着细胞内ERK信号通路的敏感性增强而增加其活性，从而导致炎症状态下对机械有害刺激的超敏反应。(C) 2004国际疼痛研究协会。Elsevier B.V.版权所有。
The mechanism of mechanical hyperalgesia in inflammation might involve a 'mechanochemical' process whereby stretch evokes the release of adenosine 5'-triphosphate (ATP) from the damaged tissue that then excites nearby primary sensory nerve terminals. In the present study, phosphorylated extracellular signal-regulated protein kinase (pERK) immunoreactivity was used as a marker indicating functional activation of primary afferent neurons to examine the P2X receptor-mediated noxious response in DRG neurons in a rat model of peripheral inflammation. We found that very few pERK-labeled DRG neurons were detected in normal rats after alpha, beta methylene-ATP (alphaBme-ATP) intraplantar injection. However, a number of DRG neurons were labeled for pERK after alphabetame-ATP injection to the complete Freund's adjuvant (CFA) induced inflamed paw. Seventy-three percent of pERK-labeled DRG neurons co-expressed the P2X3 receptor. After mechanical noxious stimulation to the hind paw of CFA-inflamed rats, we found many more pERK-labeled neurons compared to those in the normal rats. Administration of the P2X3 receptor antagonists, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid or 2'- (or 3)-O-(trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly decreased the mechanical stimulation-evoked pERK labeling in CFA-inflamed rats, but not in normal rats. We also found the recruitment of neurons with myelinated A fibers labeled for pERK in CFA-inflamed rats, which was reversed by P2X3 receptor antagonists. Moreover, TNP-ATP dose dependently reduced the mechanical hypersensitivity of CFA rats. These data suggest that the P2X receptors in primary afferent neurons increase their activity with enhanced sensitivity of the intracellular ERK signaling pathway during inflammation and then contribute to the hypersensitivity to mechanical noxious stimulation in the inflammatory state. (C) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.