Stimulus intensity, cell excitation and the N-methyl-D-aspartate receptor component of sensory responses in the rat spinal cord in vivo.

The importance of receptors for N-methyl-D-aspartate in synaptic plasticity and in triggering long-term pronociceptive changes is explained by their voltage-dependence. This suggests that their contribution to acute nociceptive responses would be determined both by the magnitude of synaptic input and by the level of background excitation. We have now examined the role of N-methyl-D-aspartate receptors in acute nociceptive transmission in the spinal cord. Drugs selectively affecting activity mediated by these receptors were tested on responses of dorsal horn neurons to noxious stimuli of different intensities and at different levels of ongoing spike discharge. The drugs used were the N-methyl-D-aspartate receptor channel blocker ketamine; the competitive antagonists, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP) and D-2-amino-5-phosphonopentanoic acid (D-AP5), and the positive modulator thyrotropin-releasing hormone. The activity of dorsal horn wide dynamic range neurons was recorded extracellularly in alpha-chloralose-anaesthetized spinalized rats. Their responses to noxious stimuli (pinch, heat and electrical) were monitored in parallel with responses to iontophoretic N-methyl-D-aspartate and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA). Drugs were given i.v. or (D-AP5) iontophoretically. At doses that selectively inhibited responses to exogenous N-methyl-D-aspartate, ketamine (4 or 8, mean 5 mg/kg i.v.) reduced the nociceptive responses of the majority of the cells in deep dorsal horn. Ketamine also reduced wind-up of the responses to repetitive electrical stimulation. Ketamine (4 or 8 mg/kg). D-CPP (2 mg/kg), D-AP5 (iontophoretically) and thyrotrophin-releasing hormone (1 mg/kg) were tested on different magnitude nociceptive responses evoked by alternating intensities of noxious heat or pinch. In percentage terms, the less vigorous responses were affected by all four drugs as much as or more than the more vigorous responses. When background activity of neurones was enhanced by continuous activation of C-fibres with cutaneous application of mustard oil, ketamine was less effective against superimposed noxious pinch responses. Ongoing background activity was affected in parallel with evoked responses. When background discharge of the cells was maintained at a stable level with continuous ejection of kainate, neither the N-methyl-D-aspartate antagonists nor thyrotrophin-relasing hormone affected the responses to noxious pinch or heat, although responses to exogenous N-methyl-D-aspartate were still blocked. The wind-up of the electrical responses was, however, reduced by ketamine irrespective of the level of background activity. The results indicate that under these conditions in vivo, N-methyl-D-aspartate receptors mediate ongoing low-frequency background activity rather than phasic high-frequency nociceptive responses. The effects of N-methyl-D-aspartate antagonists and positive modulators on nociceptive responses are evidently indirect, being secondary to changes in background synaptic excitation. These results cannot be explained simply in relation to the voltage-dependence of N-methyl-D-aspartate receptor-mediated activity; other factors, such as modulation by neuropeptides, must be involved.