What are some of the new ways to modulate the postsynaptic N methyl d aspartate ionophore?
Presynaptic release of glutamate binds to the postsynaptic glutamate receptor of the N -methyl- d -aspartate (NMDA) ionophore, resulting in channel opening and influx of sodium and calcium. This in turn results in postsynaptic depolarization and pain transmission. There have been many studies evaluating the analgesic effects of NMDA antagonists; however, there are dose-limiting side effects associated with these agents. There are several other binding sites within the ionophore channel that will modulate channel opening when glutamate binds and attempts have been made to utilize these sites to reduce side effects ( Fig. 41.1 ). A glycine binding site must be occupied in order for the channel to open. A phase II clinical trial with a glycine antagonist for neuropathic pain showed a reduction in evoked allodynia but no effect on spontaneous pain. Noncompetitive channel antagonists such as ketamine prevent channel opening but are still associated with side effects. A magnesium binding site will prevent channel opening when occupied by magnesium. The AMPA/kainate channel is linked to the NMDA ionophore and, when activated, results in a rapid influx of sodium, which will remove the magnesium block, thus allowing glutamate to open the NMDA channel. A study in healthy volunteers showed promising analgesia without side effects of an AMPA/kainate channel blocker.