D-
Serine, an endogenous coagonist of the
N-methyl-D-aspartate receptor (NMDAR), is widely distributed in the central nervous system and is synthesized from
L-serine by
serine racemase (SR). NMDAR plays an important role in
pain processing including central sensitization that eventually causes
hyperalgesia. To elucidate the roles of D-
serine and SR in
pain transmission, we evaluated the behavioral changes and spinal nociceptive processing induced by
formalin using SR knock-out (KO) mice. We found that SR is mainly distributed in lamina II of the dorsal horn of the spinal cord in wild-type (WT) mice. Although the
formalin injected subcutaneously induced the biphasic
pain response of licking in SR-KO and WT mice, the time spent on licking was significantly longer in the SR-KO mice during the second phase of the
formalin test. The number of neurons immunopositive for c-Fos and phosphorylated
extracellular signal-regulated kinase (p-ERK), which are molecular
pain markers, in laminae I-II of the ipsilateral dorsal horn was significantly larger in the SR-KO mice. Immunohistochemical staining revealed that the distribution of SR changed from being broad to being concentrated in cell bodies after the
formalin injection. On the other hand, the expression level of the cytosolic SR in the ipsilateral dorsal horn significantly decreased.
Oral administration of 10 mM D-
serine in
drinking water for one week cancelled the difference in
pain behaviors between WT and SR-KO mice in phase 2 of the
formalin test. These findings demonstrate that the SR-KO mice showed increased sensitivity to inflammatory
pain and the WT mice showed translocation of SR and decreased SR expression levels after the
formalin injection, which suggest a novel antinociceptive mechanism via SR indicating an important role of D-
serine in
pain transmission.