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NMDA receptor‐mediated synaptic transmission in the spinal dorsal horn and spinal nerve ligation‐induced nociceptive behavior are enhanced in serine racemase knockout mice
Author(s) -
Fukushima Teruyuki,
Kato Eiko,
Konno Ryuuichi,
Hori Yuuichi
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.693.11
Subject(s) - nmda receptor , neuroscience , neuropathic pain , nociception , neurotransmission , excitatory postsynaptic potential , postsynaptic potential , spinal cord , receptor , knockout mouse , chemistry , medicine , biology , inhibitory postsynaptic potential
N‐methyl‐D‐aspartate (NMDA) receptors are reported to play an important role in synaptic plasticity that may underlie not only learning and memory but also persistent pain. Peripheral nerve injury or tissue inflammation often induces an abnormal pain state, so‐called neuropathic pain. The activation of NMDA receptors mediates the development and maintenance of neuropathic pain. D‐serine co‐localizes with NMDA receptors to a high degree and acts as an endogenous coagonist of the NMDA receptor “glycine site”. D‐serine is synthesized from L‐serine by serine racemase (SR), an enzyme that is abundant in the central nervous system (CNS). To elucidate the contribution of SR to synaptic transmission in the CNS, we generated SR knockout (KO) mice. Animal experimental procedures were reviewed and approved by the institutional animal care and use committees at Dokkyo Medical University. The care and use of the animals were in accordance with the guidelines of the International Association for the Study of Pain. In the present study, we investigated NMDA receptor‐mediated synaptic transmission in the superficial dorsal horn (SDH) of spinal cord slices by means of tight‐seal whole‐cell recordings in SR‐KO mice and wild type (WT) mice. We also analyzed nociceptive behavior, which is mediated by NMDA receptors in the SDH, induced by spinal nerve ligation (SNL). The amplitude of the NMDA receptor‐mediated component of excitatory postsynaptic currents (EPSCs), normalized to that of the non‐NMDA receptor‐mediated component of EPSCs, was smaller in SR‐KO mice than in WT mice. In contrast, the time decay course and the synaptic charge transfer of the NMDA component were slower and larger in SR‐KO mice than in WT mice, respectively. Mechanical allodynia induced by the SNL was augmented in SR‐KO mice compared to WT mice. It is speculated that SR‐KO mice have a different NMDA receptor subunit composition compared to WT mice, which might explain the differences in synaptic transmission and nociceptive behaviors between the SR‐KO mice and WT mice. Real‐time RT‐PCR analysis indicated that the expression level of NR2B subunit of NMDA receptors was slightly but distinctly increased in SR‐KO mice. Finally, the present observations could suggest the possibility that the SR activity modulates the neuropathic nociception by changing the subunit composition of NMDA receptors. SR‐KO mice may provide a unique tool to investigate the synaptic action of D‐serine in the CNS.