Study for effects of D-serine on antinociception induced by acute administration of morphine

D-丝氨酸对吗啡急性给药镇痛作用的研究

• 批准号: 18591723
• 负责人: ITO Kenji
• 金额: $ 2.51万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591723/
• 关键词: D-serine; Midazolam; morphine; Serine racemase; D-amino acid oxidase; Descending Analgesic System; NMDA receptor; Benzodiazepine receptor; 鎮痛作用; 下行性痛覚抑制経路; ベンゾジアゼピン; in situ hybridization; 神経細胞; オピオイド受容体; 下行性抑制系路; グルタミン酸; 脳室内投与

We have studied the expression of serine racemase, catalyzing D-serine, and D-amino acid oxidas, metabolizing D-serine, in rat brain after acute administration of morphine.1) Acute morphine administration (10, 20, 40 mg/kg, ip) induced the mRNA expressions of serine racemase and D-amino acid oxidase 4 hours after administration.2) Serine racemase mRNA could be demonstrated predominantly in neurons of rat brain by application of in situ hybridization.3) Repeated administration of morphine for 30 days produced a significant augmentation of both the mRNA and protein expressions of serine racemase in all the brain regions, whereas no significant change in the protein expression of D-amino acid oxidase was observed in all the brain regions. Furthermore, the chronic administration caused a slight but significant elevation in the concentration of D-serine in the cortex, striatum, and hippocampus.4)The intracerebroventricular administration of midazolam alone produced hyperalgesia on the tail-flick response in a benzodiazepine receptor antagonist, flumazenil-reversible manner. The antinociception induced by the intracerebroventricular application of D-serine or morphine was attenuated by the intracerebroventricular administration of midazolam. In addition, this inhibitory effect of midazolam on the dntinociception of D-serine or morphine was antagonized by the intracerebroventricular administration of flumazenil.Together with the facts that D-serine and midazolam act as selective agonists for the glycine site of the N-methyl-D-aspartate receptor and benzodiazepine/GABAA receptor, respectively, these observations suggest a functional interaction between the NMDA and benzodiazepine/GABAA receptors in the regulation of antinociception at the supraspinal level.

我们研究了急性给药吗啡后大鼠脑中催化d -丝氨酸的丝氨酸消旋酶和代谢d -丝氨酸的d -氨基酸氧化物的表达。1)吗啡急性给药（10、20、40 mg/kg, ip）诱导大鼠丝氨酸消旋酶和d -氨基酸氧化酶mRNA表达。2)原位杂交表明丝氨酸消旋酶mRNA主要存在于大鼠脑神经元中。3)反复给药30 d后，大鼠各脑区丝氨酸消旋酶mRNA和蛋白表达均显著升高，而d -氨基酸氧化酶蛋白表达无显著变化。此外，慢性给药引起皮层、纹状体和海马中d -丝氨酸浓度的轻微但显著升高。4)脑室内单独给药咪达唑仑对苯二氮卓受体拮抗剂氟马西尼可逆方式的甩尾反应产生痛觉过敏。脑室内给药咪达唑仑可减弱d -丝氨酸或吗啡所致的抗痫作用。此外，咪达唑仑对d -丝氨酸或吗啡的抑制作用可被脑室内氟马西尼拮抗。结合d -丝氨酸和咪达唑仑分别作为n -甲基- d -天冬氨酸受体和苯二氮卓/GABAA受体甘氨酸位点的选择性激动剂的事实，这些观察结果表明NMDA和苯二氮卓/GABAA受体在脊椎上水平的抗痛觉调节中存在功能相互作用。

项目成果

Midazolam attenuates the antinociception induced by D-serine or morphine at the supraspinal level in rats

• DOI: 10.1016/j.ejphar.2008.02.068
• 发表时间: 2008-05-31
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Ito, Kenji;Yoshikawa, Masanobu;Hashimoto, Atsushi
• 通讯作者: Hashimoto, Atsushi

The expression of serine racemase mRNA in the primary culture of neuron

神经元原代培养物中丝氨酸消旋酶mRNA的表达

• 发表时间: 2007
• 作者: Akahori;Kazuhito;et. al.
• 通讯作者: et. al.

Midazolam decreases the effect of antinociception of D-serine and morphine

咪达唑仑降低 D-丝氨酸和吗啡的镇痛作用

• 发表时间: 2007
• 作者: Ito;Kenji;et. al.
• 通讯作者: et. al.

フルマゼニルはDセリンとモルヒネの鎮痛効果を増強する

氟马西尼增强D-丝氨酸和吗啡的镇痛作用

• 发表时间: 2007
• 作者: 前田 美保;他
• 通讯作者: 他

Effects of MK-801 on the expression of serine racemase and D-amino acid oxidase mRNAs and on the D-serine levels in rat brain

• DOI: 10.1016/j.ejphar.2006.09.062
• 发表时间: 2007-01-19
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Hashimoto, Atsushi;Yoshikawa, Masanobu;Kobayashi, Hiroyuki
• 通讯作者: Kobayashi, Hiroyuki