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

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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.