Anesthesia and Pain Signal transmission and Role of Ion transporters at Spinal Cord

麻醉和疼痛信号传输和离子转运蛋白在脊髓中的作用

• 批准号: 11307027
• 负责人: DOHI Shuji
• 金额: $ 13.61万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307027/
• 关键词: signaling molecules; ion transporter; Na^+-K^+ATPase inhibitor; Na^+-K^+-2Cl^-; Na^+ channels; local anesthetics; lidocaine; apotosis; PLD; PKC; PC12細胞; 疼痛シグナル; ERK; α_2-アドレナリン; K^+ATPチャネル; イオンチャネル; MAPK; ロピバカイン; シグナル伝達; TTX; Na^+チャネル

Although there have been many studies in which local anesthetic action has been examined on Na^+ channels and K^+ channels and Ca^(2+) channels, it has not been known as to roles of ion transporters such as Na^+-K^+ATPase ( Na pump ), Na^+-H^+ exchanger, Na^+-K^+-2CL cotranspoter on anesthetic action as well as pain signal transmission. Using cultured cell lines of PC12 cells and animal model with spinal catheter, we found that since their inhibitors administered into spinal subarachinoid caused significant antinociceptive action, Na^+-K^+ATPase ( Na pump ) and Na^+-H^+ exchanger would have significantrole in local anestheticaction at the spinal cord level, but not with Na^+-K^+-2CL cotranspoter. Oubabain and amiloride seem not to affect signaling molecules such as mitogen-activated protein kinase ( MAPK ) family members, extracellularsignal-regulatedkinases ( ERKs ), PKC, and PLC.On the other hand, local anesthetics affect such signaling molecules. Local anesthetic tetracaine induces apoptosis of PC12 cells via phosphorylation of MAPK family. ERK activation protects cells from death, but JNK plays the opposite role. Toxic Ca^<2+> influx caused by tetracaine seems to be responsible for apoptoticcell death, but blocking of Na^+ channels and L-type Ca^<2+> channels is unlikely involved in such tetracaine'saction on signaling molecules for apoptosis.

尽管已有许多研究对Na^+通道、K^+通道和Ca^(2+)通道的局部麻醉作用进行了研究，但对于Na^+-等离子转运蛋白的作用尚不清楚。 K^+ATP酶（Na泵）、Na^+-H^+交换器、Na^+-K^+-2CL共转运蛋白对麻醉作用以及疼痛信号传递。使用培养的PC12细胞系和脊髓导管动物模型，我们发现由于将其抑制剂施用到脊髓蛛网膜下腔中引起显着的镇痛作用，Na^+-K^+ATPase（Na泵）和Na^+-H^+交换器在脊髓水平的局部麻醉作用中具有显着作用，但与 Na^+-K^+-2CL 共转运蛋白无关。乌巴巴因和阿米洛利似乎不影响信号分子，如丝裂原激活蛋白激酶 (MAPK) 家族成员、细胞外信号调节激酶 (ERK)、PKC 和 PLC。另一方面，局部麻醉药会影响此类信号分子。局麻药丁卡因通过 MAPK 家族磷酸化诱导 PC12 细胞凋亡。 ERK 激活可以保护细胞免于死亡，但 JNK 则发挥相反的作用。丁卡因引起的有毒 Ca^<2+> 流入似乎是细胞凋亡的原因，但 Na^+ 通道和 L 型 Ca^<2+> 通道的阻断不太可能参与丁卡因对细胞凋亡信号分子的作用。

项目成果

Toshio A,Shuji D,Hiroki I: "Antinociceptive Action of Epidura K^+ATP Channel Openers via Interaction with Morphine and an de-Adrenargic"Anesth Analg. 90. 1146-51 (2000)

Toshio A、Shuji D、Hiroki I：“Epidura K^ ATP 通道开放剂通过与吗啡和去肾上腺素相互作用的镇痛作用”Anesth Analg。

Yoshihiro H,Tomoo T,Shuji D,Shigeru N,Yoshinori N: "The Effects of Pentobarbital,Isoflurane,and Propofol on Immediate-Early Gene Expression in the Vital Organs of the Rat"Anesth Analg. 90. 1177-83 (2000)

Yoshihiro H、Tomoo T、Shuji D、Shigeru N、Yoshinori N：“戊巴比妥、异氟烷和异丙酚对大鼠重要器官立即早期基因表达的影响”麻醉模拟。

Hamaya,Yoshihiro, Takeda,Tomoo, Dohi,Shyji, Nakashima,Shigeru, Nozawa,Yoshinori: "The Effects of Pentobarbitel, Isoflurane, and Propofol on Immediate-Early Gene Expression in the Vital Organs of the Rat"Anesth Analg. 90. 1177-1183 (2000)

Hamaya、Yoshihiro、Takeda、Tomoo、Dohi、Shyji、Nakashima、Shigeru、Nozawa、Yoshinori：“戊巴比妥、异氟烷和异丙酚对大鼠重要器官中立即早期基因表达的影响”麻醉模拟。

Asano,Toshio, Dohi,Shuji, Iida,Hiroki: "AntinociceptiveActionof Epidural K^+ATP Channel Openers via Interaction with Morphine and an α 2-Adrenergic Agonist in Rats"Anesth Analg. 90. 1146-1151 (2000)

Asano、Toshio、Dohi、Shuji、Iida、Hiroki：“通过与吗啡和 α 2-肾上腺素激动剂相互作用对大鼠进行硬膜外 K^+ATP 通道开放剂的镇痛作用”Anesth Analg。

Zhiming,Tan, Dohi,S., Ohguchi,K., Nakashima,S., Nozawa,Y.: "Local anesthetics inhibit muscarinic receptor-rnediatedactivation of extracellular signal-regulated kinases in rat pheochromocytoma PC12 cells"Anesthesiology. 91. 1014-1024 (1999)

志明，Tan，Dohi，S.，Ohguchi，K.，Nakashima，S.，Nozawa，Y.：“局麻药抑制大鼠嗜铬细胞瘤 PC12 细胞中毒蕈碱受体介导的细胞外信号调节激酶的激活”麻醉学。