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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.

疼痛的感觉为伤害的发生提供了有用的警告。然而，在长期炎症、手术后和神经损伤等病理条件下，外周的伤害性感受器被激活，产生自发性疼痛、痛觉过敏和触觉疼痛(超敏)。我们已经证实：1)鞘内注射前列腺素E_2和前列腺素F_2α可引起痛觉异常；2)辣椒素敏感和不敏感途径参与了痛觉异常的诱导；3)前列腺素可通过生物医学途径从突触末梢释放谷氨酸，激活→受体→，从而产生痛觉过敏。4)PGD2可阻断PGE2诱发的痛觉超敏。为了阐明特定成分在基因敲除小鼠诱发痛觉过敏中的作用，我们建立了部分坐骨神经结扎的基因敲除小鼠模型，并获得了以下结果。环氧合酶(COXS)是PG产生的限速酶。COX-1是一种结构性形式，而COX-2是一种诱导形式，被认为是炎症中PG产生的原因。1)虽然在治疗1周后出现了痛觉异常，但在COX-2^&lt；-/-&gt；小鼠中观察到了痛觉异常，提示COX-2不参与痛觉异常的诱导。2)COX-1选择性抑制剂可减轻坐骨神经损伤所致的疼痛反应，而COX-2选择性抑制剂无此作用。3)当iNOS^&lt；-/-&gt；小鼠出现痛觉超敏时，NMDA^&lt；-/-&gt；小鼠的痛觉反应消失。这些结果表明，PGE2激活的谷氨酸兴奋性传递在坐骨神经损伤后疼痛的诱导和维持中起关键作用。为了阐明痛觉异常的诱发和维持，我们将扩展坐骨神经损伤模型的研究，并将其与I.T.PG痛觉超敏模型。