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.