Intrathecal N-methyl-D-aspartate (NMDA) induces paradoxical analgesia in the tail-flick test in rats.

The intrathecal (IT) administration of NMDA in rodents has usually been reported to produce hyperalgesic reactions, although some articles describe that spinal NMDA can lead to analgesia. We show here that the nociceptive behavior (biting, scratching, licking; BSL) observed after NMDA injection (1-8 microg/rat; IT) is followed by a long period of increased tail-flick latencies, not longer detected 24 h after NMDA administration. The NMDA-receptor antagonist CPP (10-100 ng/rat; IT) blocked the BSL behavior induced by NMDA. In the tail-flick test, this antagonist induced analgesia by itself, and was able, at 30 ng/rat, to prevent the NMDA-mediated analgesia. The implication of opiate mechanisms was discarded since naloxone (3 and 10 mg/kg; IP) did not antagonize NMDA-induced analgesia. Finally, the involvement of the intracellular calcium binding protein calmodulin was assessed. The calmodulin inhibitor, calmidazolium (30-300 microg/rat; IT) only blocked the excitatory effect (BSL) without modifying the tail-flick analgesia produced by NMDA (4 microg). These results show that a single intrathecal administration of NMDA sequentially induces both nociceptive and antinociceptive, nonopiate responses in rats.