Elucidation of mechanism for induction of pain with knockout mice

阐明基因敲除小鼠诱导疼痛的机制

基本信息

批准号：
11470044
负责人：
ITO Seiji
金额：
$ 2.69万
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：
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-11470044/
关键词：
pain allodynia knockout mice sciatic nerve injury model prostaglandin cyclooxygenase NMDA receptors nitric oxide synthase プロスタグランジンD合成酵素グルタミン酸受容体 C線維シセプチン・オーファニンFQ PGE_2

项目摘要

The sensation of pain provides useful warning about occurrence of injury. However, under pathological conditions such as prolonged inflammation, post-operation, and nerve injury, nociceptors in the periphery become activeted and produce spontaneous pain, hyperalgesia and tactile pain (allodynia). We previously demonstrated that 1) intrathecal administration of prostaglandin (PG) E2 and PGF2α induced allodynia, 2) capsaicin-sensitive and-insensitive pathways were involved in induction of allodynia, 3) PGs may produce allodynia by initiating a biochamical cascade of glutamate release from synaptic terminal→activation of NMDA receptor→NO production. 4) PGD2 blocked the PGE2-induced allodynia. In order to clarify the involvement of a given component in induction of allodynia by use of knockout mice, we established partial sciatic nerve ligation method in the knockout mouse and obtained following results.Cyclooxygenases (COXs) are rate-limiting enzymes for PG production. While COX-1 is a constitutive form, COX-2 is an inducible form and considered to be accounted for PG production in inflammation. 1) Although allodynia was induced 1 week after treatment, allodynia was observed in COX-2^<-/-> mice, suggesting that COX-2 was not involved in the induction of allodynia. 2) The COX-1 selective inhibitor, but not the COX-2 selective inhibitor, alleviated pain responses induced by sciatic nerve injury. 3) While allodynia was observed in iNOS^<-/-> mice, pain responses disappeared in NMDA^<-/-> mice. These results demonstrate that excitatory transmission by glutamate activated by PGE2 plays pivotal roles in induction and maintenance of pain following sciatic nerve injury. In order to elucidate the induction and maintenance of allodynia, we will extend this study of sciatic nerve injury model and compare it with that of i.t. PG allodynia model.

疼痛的感觉提供了有关发生伤害的有用警告。然而，在病理状况（例如长时间感染，手术和神经损伤）中，周围的伤害感受器变得活跃，并产生赞助的疼痛，痛苦和触觉疼痛（合金）。我们先前证明，1）前列腺素（PG）E2和PGF2α诱导的异常动物症，2）辣椒素敏感和不敏感的途径为3）PGS可能通过启动谷氨酸级联甲酸乳腺果糖从谷氨酸级联释放的谷氨酸级别从突触末期终末→NOMDA激活的激活中产生异常性ni症。 4）PGD2阻止了PGE2诱导的异常动物症。为了阐明通过使用基因敲除小鼠的给定成分诱导的参与，我们在基因敲除小鼠中建立了部分坐骨神经结扎方法，并获得了遵循结果。循环加氧酶（COX）是PG产生的速率限制酶。尽管COX-1是一种本构形式，但COX-2是一种诱导的形式，被认为是炎症中PG产生的原因。 1）尽管在治疗后1周诱导了异常性疾病，但在Cox-2^< - / - >小鼠中观察到异常性疾病，这表明Cox-2不参与诱导异肌。 2）COX-1选择性抑制剂，但没有COX-2选择性抑制剂，减轻了坐骨神经损伤引起的疼痛反应。 3）虽然在iNOS^< - / - >小鼠中观察到异常性症，但疼痛反应消失在NMDA^< - / - >小鼠中。这些结果表明，在坐骨神经损伤后，PGE2激活的谷氨酸兴奋性传播在诱导和维持疼痛中起关键作用。为了阐明异常性疾病的诱导和维持，我们将扩展这项坐骨神经损伤模型的研究，并将其与I.T. PG异常性nia模型。