Heterozygous mice mutant for the NMDA-type glutamate receptor (GluR) epsilon2 subunit with a highly homogeneous genetic background showed exaggerated responses to various acute noxious stimuli in the footshock, tail-flick, hot-plate and tail-pinch tests. Because the noxious stimuli in these behavioral tests were electrical, thermal and mechanical, the reduction of GluRepsilon2 proteins exerted stimulatory effects on acute nociceptive responses across modalities. Previous studies showed that GluRepsilon1 and GluRepsilon4 subunit mutant mice exhibited no alteration in the responses to acute noxious stimuli. Thus, among NMDA receptor subunits, the GluRepsilon2 subunit specifically plays an important role in the regulation of the acute nociceptive responses.