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

我们研究了急性吗啡给药后大鼠脑中催化D-丝氨酸的丝氨酸消旋酶和代谢D-丝氨酸的D-氨基酸氧化酶的表达。（10、20、40 mg/kg，ip）给药后4 h诱导丝氨酸消旋酶和D-氨基酸氧化酶mRNA表达。原位杂交结果显示丝氨酸消旋酶mRNA主要分布于大鼠脑神经元中。吗啡重复给药30天，在所有的海马组织中，丝氨酸消旋酶的mRNA和蛋白质表达均显著增加。而在所有脑区中未观察到D-氨基酸氧化酶蛋白表达的显著变化。此外，长期给药引起皮质、纹状体和海马中D-丝氨酸浓度轻微但显著的升高。4）单独脑室内给药咪达唑仑以苯二氮卓类受体拮抗剂氟马西尼可逆的方式产生甩尾反应的痛觉过敏。侧脑室注射咪达唑仑可减弱D-丝氨酸或吗啡的镇痛作用。此外，咪达唑仑对D-丝氨酸或吗啡的dnt伤害性感受的这种抑制作用可被氟马西尼的脑室内给药所拮抗，连同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类/GABAA受体的甘氨酸位点的选择性激动剂的事实，这些观察结果表明，在脊髓上水平的抗伤害感受调节中，NMDA和苯二氮/GABAA受体之间存在功能性相互作用。

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.