COOPERATIVE INTERACTION AMONG THE VARIOUS REGULATORY SITES WITHIN THENMDA RECEPTOR-CHANNEL COMPLEX IN MODULATING THE EVOKED-RESPONSES TO NOXIOUS THERMAL STIMULI OF SPINAL DORSAL HORN NEURONS IN THE CAT

Interactions among antagonists acting at different regulatory sites wi thin the N-methyl-D-aspartate (NMDA) receptor-channel complex on the e voked responses to noxious thermal stimuli of wide dynamic range (WDR) neurons in spinal dorsal horn were studied on 21 adult anesthetized a nd spinalized cats. The responses of nociceptive spinal dorsal horn ne urons to noxious heating (45-55 degrees C) of the glabrous skin of the unilateral hind paw were reduced markedly by iontophoretically applie d antagonists. The specific recognition site antagonist, DL-2-amino-5- phosphonovaleratic acid (APV), the strychnine-insensitive glycine site antagonist 7-chlorokynurenic acid (7CKA), the polyamine site antagoni st ifenprodil (IFEN), and the phencyclidine (PCP) site antagonists ket amine (KET) and MK-801 (40-100 nA) significantly reduced (t-tests, P < 0.01) the noxious thermal stimulus-evoked responses in about 70% of t he neurons by (mean +/- SE) 54.1 +/- 5.8% (n = 19), 80.8 +/- 4.7% (n = 16), 51.1 +/- 6.4% (n = 10), 77 +/- 4.9% (n = 16) and 81.2 +/- 8.1% ( n = 5), respectively. APV and IFEN were less effective in blocking nox ious thermal stimuli-evoked responses than 7CKA, KET and MK-801 (ANOVA , P < 0.05). The responses were completely inhibited in some neurons. After co-administration of the antagonists, APV + 7CKA, APV + IFEN, 7C KA + IFEN, APV + KET and APV + MK-801, all at the subthreshold ejectio n current, the responses were reduced markedly in 13 of 16, 7 of 10, 5 of 10, 3 of 6 and 3 of 5 neurons, respectively. The present study sug gests that blockage of any component of the NMDA receptor-channel comp lex antagonizes the NMDA receptor-mediated response, and that there ar e the cooperative interactions among the various regulatory sites with in the NMDA receptor-channel complex in the transmission or modulation of spinal nociceptive thermal information.