Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice

Abstract

Intrathecal (i.t.) injection of the competitive and selective N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-5-phosphonopentanoic acid (AP5), D-2-amino-7-phosphonoheptanoic acid (AP7), β-D-aspartylaminomethyl phoshonic acid (Asp-AMP), 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and γ-D-glutamylaminomethyl phosphonic acid (Glu-AMP) produced dose-dependent and reversible analgesic effects in the mouse hot-plate and formalin tests of pociception. They were slightly more potent in the formalin test but had no or negligible effects in the tail-flick test. The non-selective or non-NMDA receptor antagonists 6-cyano-7-nitro-quinoxalinedione (CNQX), 6,7-dinitro-quinoxalinedione (DNQX), γ-D-glutamylglycine (γDGG), γ-glutamylaminomethyl sulphonic acid (GAMS), kynurenic acid, cis-2,3-piperidine dicarboxylic acid (cis-PDA; partial agonist) and p-bromobenzoyl piperazine dicarboxylic acid (pBB-PzDA) had the same efficacy in the mouse hot-plate, tail-flick and formalin tests (γDGG and pBB-PzDA were not testeed in the formalin test). This heterogeneous group of antagonists was somewhat more potent in the tail-flick test and slightly less potent in the formalin test than in the hot-plate test. Of the two glycine site antagonists tested, 7-chlorokynurenic acid (7-Cl-Kyyn) and (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), the effect of the latter was compatible with selective action at the NMDA receptor complex while the action of the former was comparable to those of non-selective excitatory amino acid (EAA) receptor antagonists. The non-competitive NMDA receptor antagonists ketamine, phencyclidine (PCP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) were without effect in the hot-plate and tail-flick tests when tested alone, but ketamine and PCP potentiated the effect of DNQX in these tests. High doses of PCP and MK-801 produced effects in the formalin test. At high doses, all of the EAA receptor antagonists impaired the motor function of the mice. These results show that EAA receptor antagonists acting at both NMDA and non-NMDA receptors produce dose-dependent and reversible antinociceptive effects. Antagonists that selectively block the NMDA receptor complex have a different profile in the nociceptive tests than the non-selective receptor antagonists.