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Study on the inflammatory mediators and intracellular signal transmission involved in the peripheral sensitization of nociceptors

伤害性感受器外周敏化过程中炎症介质及细胞内信号传递的研究

基本信息

批准号：
06680807
负责人：
MIZUMURA Kazue
金额：
$ 1.15万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Hyperalgesia is commonly observed in the inflamed region. One mechanism of the hyperalgesia is considered to be sensitization of peripheral nociceptors. The aim of this project is to clarify this sensitizing mechanism by studying 1) release of inflammatory mediators into the lightly burned (55ﾟC or 66ﾟC for 30s) air pouch, 2) effects of inflammatory mediators, especially of histamine, on the polymodal receptor, a type of nociceptor. In addition, histamine receptor subtypes and intracellular signal transmission were studied. Following results were obtained : 1) Bradykinin content in the exudate of the burned rat air pouch measured by ELISA tended to increase at 20 min after burn, peaked at 40 min, and then decreased. 2) The heat response of polymodal receptors recorded from canine in vitro superiorspermatic nerve preparations was sensitized by histamine >= 10 muM concentration-dependently. This effects was mediated through H1 receptor. To clarify involvement of protein kinase C,which is known to be activated through H1 receptor, in the histamine-induced sensitization of the heat response, effects of phorbol 12,13-dibutyrate (PDBu), a phorbol ester, was studied. PDBu excited a part of polymodal receptors >= 100 nM,and sensitized their heat response >= 10 nM concentration dependently. This sensitizing effect was blocked by treatment of staurosporine, a protein kinase inhibitor. Thus, it is highly possible that activation of protein kinase C induces sensitization of the heat response. The bradykinin response was, however, suppressed by pretreating PDBu 0.1 muM,but facilitated by simultaneously applying PDBu with bradykinin. In addition, the bradykinin response was suppressed by staurosporine. These results suggest that protein kinase C activation is implicated in the bradykinin response, and there also exist a process which is desensitized by protein kinase C.

痛觉过敏通常见于炎症部位。痛敏的一种机制被认为是外周伤害性感受器的敏化。本项目的目的是通过研究1)炎症介质向轻度烧伤(55ﾟC或66ﾟC持续30s)气囊的释放，2)炎症介质，特别是组胺对伤害性感受器多模式受体的影响来阐明这种增敏机制。此外，还研究了组胺受体亚型和细胞内信号传递。结果表明：(1)用双抗体夹心法测定大鼠烧伤后20min气囊渗出液中缓激肽含量呈上升趋势，40min达高峰，然后下降。2)组胺可浓度依赖性地敏化犬精索上神经标本记录的多通道受体的热反应。这种作用是通过H1受体介导的。为了阐明已知通过H1受体激活的蛋白激酶C参与组胺诱导的热反应敏化，研究了佛波酯12，13-二丁酸酯(PDBu)的作用。PDBu可兴奋部分多通道受体，并呈浓度依赖性地敏化其热反应。这种增敏作用可被蛋白激酶抑制剂星形孢子素阻断。因此，蛋白激酶C的激活极有可能导致热反应的敏化。然而，PDBu 0.1um可抑制缓激肽的反应，而同时应用PDBu和缓激肽则可促进缓激肽的反应。此外，星状孢子素抑制了缓激肽的反应。这些结果表明，蛋白激酶C的激活与缓激肽的反应有关，并且还存在一个被蛋白激酶C脱敏的过程。