Raigorodsky G, Urca G
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
Eur J Pharmacol. 1990 Jun 21;182(1):37-47. doi: 10.1016/0014-2999(90)90491-n.
Blockade of N-methyl-D-aspartate (NMDA) receptors in the spinal cord of rodents has been shown to produce antinociceptive effects and motor impairment. To find out whether other receptors for excitatory amino acids (EAA) can influence spinal pathways utilizing the NMDA receptors we compared, in mice, the behavioral consequences of intrathecal injection of four EAA antagonists, 2-amino-5-phosphono valerate (APV), kynurenate, gamma-D-glutamyl glycine (DGG) and glutamylaminomethyl sulphonate (GAMS). The selectivity of these antagonists at different concentrations was evaluated behaviorally by assessing their ability to block the biting behavior elicited by intrathecal EAA agonists. Blockade of the NMDA receptor was necessary to elicit antinociceptive effects and motor impairment. Thus, APV produced antinociception at concentrations selective for the action of NMDA. The wide spectrum EAA antagonists, DGG and kynurenate, and the quisqualate/kainate antagonist, GAMS, all produced antinociception and motor impairment at concentrations which also blocked NMDA-induced bites. However, an inhibitory modulation of the action of NMDA by quisqualate-sensitive systems was also observed. Thus, high concentrations of APV (greater than 1 mM), which also blocked quisqualate-elicited bites, produced a surprising, sharp decrease in APV antinociception and motor impairment, effects which were reversed by quisqualate. Furthermore, quisqualate significantly inhibited NMDA-induced bites. Additional evidence for such an inhibitory-modulatory effect of quisqualate can be gathered from the antinociceptive potency of DGG. This antagonist, which blocks the action of both NMDA and quisqualate, was less potent as an antinociceptive agent than APV. No such discrepancy between the ability to inhibit the action of NMDA and to elicit antinociceptive effects and motor impairment was noted for either kynurenate or GAMS. Evidence is provided that these different profiles of action are due to the fact that DGG and high concentrations of APV act at different subpopulations of quisqualate receptors than do kynurenate and GAMS, and that the former subpopulation is involved in the modulation of the action of NMDA.
在啮齿动物脊髓中阻断N-甲基-D-天冬氨酸（NMDA）受体已显示出产生抗伤害感受作用和运动障碍。为了弄清楚兴奋性氨基酸（EAA）的其他受体是否会影响利用NMDA受体的脊髓通路，我们在小鼠中比较了鞘内注射四种EAA拮抗剂（2-氨基-5-磷酸戊酸（APV）、犬尿烯酸、γ-D-谷氨酰甘氨酸（DGG）和谷氨酰胺甲基磺酸盐（GAMS））后的行为后果。通过评估它们阻断鞘内EAA激动剂引发的咬行为的能力，从行为学角度评估了这些拮抗剂在不同浓度下的选择性。阻断NMDA受体是产生抗伤害感受作用和运动障碍所必需的。因此，APV在对NMDA作用具有选择性的浓度下产生抗伤害感受作用。广谱EAA拮抗剂DGG和犬尿烯酸，以及quisqualate/海人藻酸拮抗剂GAMS，在阻断NMDA诱导的咬行为的浓度下均产生抗伤害感受作用和运动障碍。然而，也观察到quisqualate敏感系统对NMDA作用的抑制性调节。因此，高浓度的APV（大于1 mM），它也阻断quisqualate引发的咬行为，却使APV的抗伤害感受作用和运动障碍惊人地急剧下降，这些作用可被quisqualate逆转。此外，quisqualate显著抑制NMDA诱导的咬行为。quisqualate这种抑制性调节作用的更多证据可从DGG的抗伤害感受效力中收集。这种拮抗剂同时阻断NMDA和quisqualate的作用，作为抗伤害感受剂的效力比APV弱。对于犬尿烯酸或GAMS，在抑制NMDA作用的能力与引发抗伤害感受作用和运动障碍之间未发现这种差异。有证据表明，这些不同的作用模式是由于DGG和高浓度的APV作用于与犬尿烯酸和GAMS不同的quisqualate受体亚群，并且前一个亚群参与了对NMDA作用的调节。
