Elucidation of Mechanism of Pain Transmission by Gene Targeting

通过基因靶向阐明疼痛传递机制

基本信息

批准号：
09480168
负责人：
ITO Seiji
金额：
$ 4.22万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

Prolonged inflammation and nerve injury often lead to chronic pain such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). With the advent of molecular biology, substance P and glutamate have been shown to be involved in acute pain and hyperalgesia, but a factor(s) involving allodynia had remained to be known. We found that intrathecal administration of prostaglandin E_2 induced allodynia in conscious mice and established an in vivo allodynia model. These several years, we have pharmacologically elucidated the mechanism of allodynia by use of receptor agonists and antagonists. Here, we applied this model to mice lacking lipocalin-type PGD synthase (L-PGDS) and obtained following results.While hyperalgesia induced by PGD_2 and PGE_2 was observed in L-PGDS-/- mice as well as wild-type mice, PGE_2-induced allodynia was not observed in L-PGDS-/-. Simultaneous administration of a femtogram amount of PGD_2 with PGE_2 induced allodynia in L-PGDS-/- m … More ice to the same extent as in wild-type mice. These results demonstrate that POD_2 is essential for induction of PGE_2-induced allodynia. Because PGD_2 blocked PGE_2-induced allodynia at a pg level, these experiments with PGDS-/- knockout mice first demonstrate that PGD_2 may regulate the induction of PGE_2-induced allodynia biphasically. Furthermore, the inhibitory amino acid GABA was suggested to mediate the action of PGD_2. At present experiments with knockout mice lacking other PG synthases and PG receptors are under investigation. Until recently, it was generally accepted that PGs act on pain transmission in the periphery and that opioids act, in the central nervous system. With the aid of developmental technology and genetargeting techniques, we have shown that both POs and opioids play important roles in induction of allodynia at the molecular level. We have recently succeeded in isolation of a novel peptide nocistatin from the brain and the cloning and characterization of its receptor are in progress. Less

长期的炎症和神经损伤通常会导致慢性疼痛，例如有害刺激会引起痛觉过敏，而无害的触觉刺激会引起疼痛（异常性疼痛）。随着分子生物学的出现，P物质和谷氨酸已被证明与急性疼痛和痛觉过敏有关，但是。我们发现鞘内注射前列腺素 E_2 可在清醒小鼠中诱导异常性疼痛，并建立体内异常性疼痛。近年来，我们通过使用受体激动剂和拮抗剂从药理学角度阐明了异常性疼痛的机制，在此，我们将该模型应用于缺乏脂质运载蛋白型PGD合酶（L-PGDS）的小鼠，并获得了以下结果。在L-PGDS-/-小鼠和野生型小鼠中均观察到PGD_2和PGE_2，在L-PGDS-/-中未观察到PGE_2诱导的异常性疼痛。同时施用飞克量的 PGD_2 和 PGE_2 在 L-PGDS-/- m … More 冰中诱导异常性疼痛，其程度与野生型小鼠相同。这些结果表明 POD_2 对于诱导 PGE_2 诱导的异常性疼痛至关重要。 PGD_2 在 pg 水平上阻断 PGE_2 诱导的异常性疼痛，这些使用 PGDS-/- 敲除小鼠的实验首先证明 PGD_2 可以调节异常性疼痛的诱导此外，抑制性氨基酸 GABA 被认为介导 PGD_2 的作用，目前正在研究缺乏其他 PG 合酶和 PG 受体的敲除小鼠的实验，直到最近，人们普遍认为 PG 会作用于 PGE_2。借助发育技术和基因靶向技术，我们已经证明 PO 和阿片类药物在中枢神经系统中发挥重要作用。我们最近成功地从大脑中分离出一种新型肽 nocistatin，其受体的克隆和表征正在进行中。