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Studies on Mechanism of Intractable Pain wih Animal Models

顽固性疼痛的动物模型机制研究

基本信息

批准号：
11470329
负责人：
MINAMI Toshiaki
金额：
$ 9.98万
依托单位：
Osaka Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470329/
关键词：
allodynia pain nocistatin nociceptin glutamate receptor prostaglandins knockout mice カプサイシン NMDA 痛覚過敏反応

项目摘要

Mechanism of PG-induced allodyniaWe previously showed that intrathecal (i.t.) administration of PGE 2 and PGF2αinduce touch-evoked pain (allodynia) in conscious mice. Selective elimination of C-fibers by neonatal capsaicin treatment results in the disappearance of allodynia induced by PGE 2, but not byPGF2α. PGE2- induced allodynia was not observed in NMDA receptor ε1 subunit knockout mice and sensitive to morphine. In contrast, PGF2α-induced one was not observed in NMDA ε4 subunit knockout mice and insensitive to morphine. The induction of allodynia by PGE 2 was abolished by the NMDA, receptor ε2 antagonist CP-101, 606. PGF2 α-induced allodynia was not affected by CP- 101, 606. These results demonstrate that there are two pathways for induction of allodynia mediated by the glutamatergic system.Roles of nociceptin and nocistatin in pain transmissionWe recently showed that i.t. administration of nociceptin induced thermal hyperalgesia and tactile allodynia. In the present study, we demonstrate that capsaicin-sensitive primary afferent fibers are involved not only in thermal hyperalgesia but also in tactile allodynia induced by nociceptin, but in different pathways ; the former is mediated by substance P and the latter is mediated by glutamate through the NMDA receptor comprising GluR ε1 subunit. On the other hand, nocistatin is derived from the same precursor as nociceptin, and it has biological activity which blocks the nociceptin- and PGs-evoked pain responses. Furthermore nocistatin blocks both the early and the late phases in the formalin test.

PG诱发异常性疼痛的机制我们先前表明鞘内（i.t.）给药PGE 2和PGF 2 α诱导清醒小鼠触觉诱发痛（异常性疼痛）。用新生儿辣椒素治疗选择性消除C纤维可使PGE 2引起的痛觉超敏消失，但不能使PGF 2 α引起的痛觉超敏消失。NMDA受体ε1亚基敲除小鼠未观察到PGE 2诱导的异常性疼痛，且对吗啡敏感。而PGF 2 α诱导的NMDA ε4亚基基因敲除小鼠则无此效应，且对吗啡不敏感。PGE 2诱发的痛觉超敏反应可被NMDA受体拮抗剂CP-101，606阻断。PGF 2 α诱导的异常性疼痛不受CP- 101的影响，606。这些结果表明，有两个途径诱导异常性疼痛介导的神经系统。施用伤害感受素诱导热痛觉过敏和触觉异常性疼痛。在本研究中，我们证明，辣椒素敏感的初级传入纤维不仅参与热痛觉过敏，但在不同的途径，前者是由P物质介导的触觉异常性疼痛，后者是由谷氨酸通过NMDA受体的GluR ε1亚基介导的。另一方面，nocistatin与nociceptin衍生自相同的前体，并且其具有阻断nociceptin和PGs诱发的疼痛反应的生物活性。此外，在福尔马林试验中，nocistatin阻断早期和晚期相。