The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones

The voltage dependence and channel-blocking kinetics of uncompetitive NMDA receptor antagonists have been well-described using in vitro techniques, bu t there is little evidence concerning the functional significance of these properties in vivo. We have now compared the effects of NMDA antagonists th at display varied profiles of voltage-dependent block in vitro, on response s of spinal neurones in anaesthetised rats. The compounds examined were the uncompetitive channel blockers memantine, ketamine and MK-801 and, for com parison, an antagonist that acts at the strychnine insensitive glycine bind ing site (MRZ 2/502). Using frequency of spike discharge as an indicator of somatic depolarisation, we have compared the effects of these antagonists on responses evoked by iontophoretic NMDA application and on synaptic respo nses evoked by pinch or electrical stimulation (the latter eliciting "wind- up"). The effectiveness of the antagonists was directly but variably relate d to the discharge frequency of the test response. The rank order of depend ence on firing rate matched the rank order of voltage dependence reported i n vitro, namely: memantine > ketamine > MK-801 greater than or equal to MRZ 2/502. Doses that reduced responses to iontophoretic application of NMDA w ere less effective at reducing responses to pinch, perhaps due to the major non-NMDA component of the synaptic response. Memantine preferentially redu ced "wind-up" relative to responses to pinch, whereas ketamine and MK-801 r educed both types of synaptic responses in parallel. This "filtering" by lo w affinity, voltage-dependent NMDA antagonists such as memantine. of non-ph ysiological activity whilst leaving normal synaptic events relatively untou ched, may contribute to their more favourable clinical profile. (C) 2001 El sevier Science Ltd. All rights reserved.