STIMULUS-INTENSITY, CELL EXCITATION AND THE N-METHYL-D-ASPARTATE RECEPTOR COMPONENT OF SENSORY RESPONSES IN THE RAT SPINAL-CORD IN-VIVO

Thr importance of receptors for N-methyl-D-aspartate in synaptic plast icity 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 n ow examined the role of N-methyl-D-aspartate receptors in acute nocice ptive transmission in the spinal cord. Drugs selectively affecting act ivity mediated by these receptors were tested on responses of dorsal h orn neurons to noxious stimuli of different intensities and at differe nt levels of ongoing spike discharge. The drugs used were the N-methyl -D-aspartate receptor channel blocker ketamine; the competitive antago nists, 3-((R)-2-carboxypiperazin-4yl)-propyl-1 -phosphonic acid (D-CPP ) and D-2-amino-5-phosphonopentanoic acid (D-AP5), and the positive mo dulator thyrotropin-releasing hormone. The activity of dorsal horn wid e dynamic range neurons was recorded extracellularly in alpha-chloralo se-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 pha-amino-3-hydroxy-5-methyl -4-isoxazole-propionic acid (AMPA). Drugs were given i.v. or (D-AP5) i ontophoretically. At doses that selectively inhibited responses to exo genous N-methyl-D-aspartate, ketamine (4 or 8, mean 5 mg/kg i.v.) redu ced the nociceptive responses of the majority of the cells in deep dor sal 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-A P5 (iontophoretically) and thyrotrophin-releasing hormone (1 mg/kg) we re tested on different magnitude nociceptive responses evoked by alter nating 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 neu rones was enhanced by continuous activation of C-fibres with cutaneous application of mustard oil, ketamine was less effective against super imposed noxious pinch responses. Ongoing background activity was affec ted in parallel with evoked responses. When background discharge of th e cells was maintained at a stable level with continuous ejection of k ainate, neither the N-methyl-D-aspartate antagonists nor thyrotrophin- relasing hormone affected the responses to noxious pinch or heat, alth ough responses to exogenous N-methyl-D-aspartate were still blocked. T he wind-up of the electrical responses was, however, reduced by ketami ne irrespective of the level of background activity. The results indic ate that under these conditions in vivo, N-methyl-D-aspartate receptor s mediate ongoing low-frequency background activity rather than phasic high-frequency nociceptive responses. The effects of N-methyl-D-aspar tate 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 th e voltage-dependence of N-methyl-D-aspartate receptor-mediated activit y; other factors, such as modulation by neuropeptides, must be involve d. (C) 1997 IBRO. Published by Elsevier Science Ltd.