Spinal antinociceptive effects of excitatory amino acid antagonists: quisqualate modulates the action of N-methyl-D-aspartate.

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.

Involvement of N-methyl-D-aspartate receptors in nociception and motor control in the spinal cord of the mouse: behavioral, pharmacological and electrophysiological evidence.

The present study evaluated, using behavioral and electrophysiological methods, the involvement of the N-methyl-D-aspartate receptor in the processing of noxious information in the spinal cord of the mouse. The selectivity of the excitatory amino acid antagonists 2-amino-5-phosphonovalerate and glutamylaminomethylsulphonate was assessed behaviorally, using their ability to reverse the biting behavior elicited by intrathecal excitatory amino acid administration as a tool. 2-Amino-5-phosphonovalerate at concentrations up to 1 mM was shown to be selective for the N-methyl-D-aspartate receptor, while glutamylaminomethylsulphonate was selective for the kainate and quisqualate receptors at similar concentrations. At these concentrations, intrathecal administration of 2-amino-5-phosphonovalerate to awake mice produced significant analgesia on a battery of tests, as well as a dose-related motor impairment, while glutamylaminomethylsulphonate was without effect. Proof that 2-amino-5-phosphonovalerate exerts its effects via N-methyl-D-aspartate receptors is that glutamylaminomethylsulphonate, at concentrations which also block this receptor (greater than 1 mM), also produced analgesia and motor effects. Furthermore, N-methyl-D-aspartate, but not kainate or quisqualate, reversed the analgesic effects of 2-amino-5-phosphonovalerate. In fact, significant potentiation of analgesia could be seen with quisqualate. In accordance with the behavioral pharmacological data, topical application of 2-amino-5-phosphonovalerate onto the spinal cord of anesthetized mice significantly depressed the response of spinal sensory neurons to noxious mechanical and electrical stimulation, but did not affect the activity of neurons which showed no preferential reaction to noxious stimulation. Glutamylaminomethylsulphonate at non-analgesic concentrations was without effect. Based on these and other studies we conclude that N-methyl-D-aspartate receptor bearing interneurons participate in nociception, and that N-methyl-D-aspartate antagonists exert their analgesic and motor effect by changing the tone of spinal neural action in the spinal cord, rather than direct intervention in primary afferent transmission.

Behavioral classification of excitatory amino acid receptors in mouse spinal cord.

Intrathecal injections of excitatory amino acid (EAA) agonists to the spinal cord of mice produces behavioral activation manifest as biting and scratching of the hindquarters. The dose-response relationship of EAA (N-methyl-D-aspartate (NMDA), kainate, quisqualate and glutamate)-induced activation revealed qualitative and quantitative differences in their pattern of action, suggesting that these agonists act at distinct receptors. Evaluation of the blockade of EAA-induced bites by a series of antagonists: DL-2-amino-5-phosphonovalerate (APV), gamma-D-glutamyl glycine (DGG), kynurenate and glutamylaminomethylsulphonate (GAMS), indicated that selective activation of the NMDA, quisqualate and kainate receptors can be demonstrated using this behavior. The NMDA receptors could be subdivided on the basis of different sensitivity to kynurenate and APV. Antagonist-resistant components of both kainate and quisqualate action were also shown. Thus, the biting behavior induced by the administration of intrathecal EAA agonists can be used as a relatively selective behavioral tool for assessing the pharmacological profile of action of excitatory amino acid agonists and antagonists in the spinal cord.

Intrathecal N-methyl-D-aspartate (NMDA) activates both nociceptive and antinociceptive systems.

Injection of the excitatory amino acid N-methyl-D-aspartate (NMDA) into the spinal subarachnoid space of rats produces both hyperalgesic and analgesic effects. At lower concentrations (0.5 mM) little behavioral effect is elicited by the drug. However, brief hyperalgesia followed by several minutes of analgesia can be detected in these animals. Higher concentrations of the drug produce vocalization, caudally directed scratching and biting and hyper-responsiveness to light touch. The NMDA antagonist, arginine vasopressin, produces analgesia when injected by itself and completely reverses all effects of NMDA. NMDA-induced analgesia, but not hyperalgesia, is reversed by intrathecal administration of naloxone, methysergide and phentolamine. The analgesic effects of both agonist and antagonist are markedly potentiated by spinalization. These results suggest the involvement of NMDA receptors in both the transmission of pain and the mediation of spinal segmental pain inhibitory mechanism.