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N-ethylmaleimide-sensitive fusion protein (NSF) is involved in central sensitization in the spinal cord through GluR2 subunit composition switch after inflammation


Dr S. Ito, as above.


Central sensitization, similar to long-term potentiation in the hippocampus, refers to the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord following tissue injury or nerve damage. In the course of inflammation, many proteins including glutamate receptors are assumed to be dynamically reorganized in the postsynaptic density (PSD) and involved in persistent pain. Mechanical hyperalgesia induced by intraplantar injection of complete Freund’s adjuvant (CFA) was inhibited at 4 h, but not at 24 h, by indomethacin, an inhibitor of prostanoid synthesis. To elucidate the nature of the molecule(s) involved in the late phase of inflammatory pain, we analysed the PSD fraction prepared from the lumbar spinal cord of rats before and 24 h after CFA injection by conducting two-dimensional differential gel electrophoresis. N-ethylmaleimide-sensitive fusion protein (NSF) was identified as a downregulated protein in the PSD by MALDI-TOF MS and immunoblotting. Concomitant with the decrease in NSF, GluR2 and GluR3 were decreased and GluR1 was conversely increased in the PSD fraction 24 h after CFA injection. In vivo patch-clamp recordings of rats 24 h after CFA injection showed that excitatory postsynaptic currents of dorsal horn neurons evoked by pinch stimuli to inflamed skin were inwardly rectified and inhibited by 60% by philanthotoxin-433, a selective inhibitor of the Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These results suggest that peripheral inflammation gives rise to central sensitization in the spinal cord through subunit composition switch of AMPA receptors in the late phase.