Supraspinal vs spinal sites of the antinociceptive action of the subtype-selective NMDA antagonist ifenprodil

The N-methyl-D-aspartate (NMDA) antagonist ifenprodil and several structura lly related compounds are highly selective for the NR2B-containing receptor subtype. This selectivity could provide an explanation for the reported di fference of the analgesic and side-effect profile of ifenprodil-like compou nds from other NMDA antagonists. In this work, we have queried if the ifenp rodil-induced antinociception can be attributed to the block of NMDA recept ors in the spinal cord. Ifenprodil and some other NMDA antagonists (MK-801, memantine) were tested in a model of inflammatory pain (Randall-Selitto) i n rats. The in vivo NMDA antagonism was assessed in anaesthetised rats on r esponses of spinal dorsal horn (DH) neurones to iontophoretic NMDA and in t he model of single motor unit (SMU) wind-up. Ifenprodil, MK-801 and memanti ne dose-dependently increased nociceptive thresholds in the Randall-Selitto model. Antinociceptive doses of the channel blockers selectively antagonis ed NMDA responses of DH neurones and inhibited wind-up. In contrast, antino ciceptive doses of ifenprodil did not show any NMDA antagonism in electroph ysiological tests. Although ifenprodil did not inhibit the SMU responses to noxious stimuli in spinalised rats, it markedly and dose-dependently inhib ited nociceptive SMU responses in sham-spinalised rats. These results argue against the spinal cord being the principal site of antinociceptive action of ifenprodil; supraspinal structures seem to be involved in this effect. (C) 2000 Elsevier Science Ltd. All rights reserved.