Enhanced nociception by exogenous and endogenous substance P given into the spinal cord in mice lacking NR(2)A/epsilon(1), an NMDA receptor subunit.

In capsaicin-pretreated mice, the nociceptive responses induced by intrathecally (i.t.) administered substance P (SP) were enhanced by N-methyl-D-aspartate (NMDA)-type receptor antagonists, dizocilpine (MK801) and D-2-amino-5-phosphonopentanoate (D-AP5) in a dose-dependent manner. Similar enhancement of SP-induced nociception was also observed in mice lacking the NMDA-type glutamate receptor NR2A/epsilon(1) subunit gene (GluRepsilon(1)(-/-) mice). On the other hand, GluRepsilon(1)(-/-) mice showed a marked enhancement of the peripheral nociceptive responses induced by intraplantar (i.pl.) injection of SP and bradykinin (BK). As the nociceptive responses to SP and BK (i.pl.) were both antagonized by CP-99994, an neurokinin(1) (NK(1)) antagonist (i.t.), these results suggest that GluRepsilon(1) receptor may play an inhibitory role in the downstream mechanisms of primary nociceptive SP neurones, possibly through activation of unidentified inhibitory neurones.