The purpose of this study was to determine whether D-serine, an endogenous N-methyl-D-aspartate (NMDA) receptor agonist, enhances nociception at the spinal level, as compared with the nociceptive effect of glycine. The following drugs were injected intrathecally through a previously implanted polyethylene tube in rats: 10 µl of physiological saline as control; 2 pmol, 2 µmol, or 2 mmol of D-serine or L-serine; 10 µmol of glycine; and 5 pmol of strychnine. Formalin (0.625% and 1.25%, 50 µl) was injected subcutaneously into the left hind paw 15 min after each agent. The number of flinches was counted as nociceptive behavior in the early phase (0 - 10 min), first late phase (11 - 30 min), and second late phase (31 - 60 min) after injection of formalin. Flinching occurred only during the early stage after the injection of 0.625% formalin. All doses of D-serine, however, significantly restored late stages of the flinching response after injection of 0.625% formalin. In rats given an injection of 1.25% formalin, the lowest and middle dose levels of D-serine significantly potentiated both first and second late stages of the flinching response. Treatment with L-serine had no significant effect on the flinching responses induced by 0.625% or 1.25% formalin. In contrast, injection of 10 µmol glycine significantly decreased the total number of flinches during the late phase, and this response was antagonized by treatment with 5 pmol strychnine. Our results indicate that D-serine in the spinal cord is closely involved in the modulation of inflammatory pain and that its role in nociception differs from that of glycine.
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