The recent literature on the antinociceptive action of
ionotropic glutamate receptor antagonists is reviewed with special emphasis on their clinical potential. Actually the glutamatergic pathways descending from the brain stem into the spinal cord may generate
analgesia. However, physiologically more important is that
glutamate and
aspartate are apparently the main
neurotransmitters along the ascending nociceptive pathways in the spinal cord.
Glutamate,
aspartate and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae (I, II) of the spinal cord. In low doses
glutamate receptor antagonists only slightly elevate the threshold of the physiological
pain sensation. However, they suppress the process of pathological sensitisation i.e. lowering of the pain threshold seen upon excessive or lasting stimulation of C-fibre afferents, a process that takes place during
inflammation or other kinds of tissue injury. At electrophysiological level antagonists of both the
NMDA- and
AMPA/
kainate receptors inhibit wind up i.e. lasting activation of the polymodal, second-order sensory neurones in the deeper layers of the dorsal horn. During sensitisation the resting Mg(++) blockade of transmembrane Ca(++) channels is abolished, certain second messenger pathways are activated, the transcription of many genes is enhanced leading to overproduction of
glutamate and other excitatory
neurotransmitters and expression of Na(+) channels in the primary sensory neurones activated at lower level of depolarisation. This cascade of events leads to increased excitability of the
pain pathways.
NMDA antagonists are apparently more potent in experimental models of
neuropathic pain, whereas
AMPA antagonists are more effective in abolition of
hyperalgesia seen during experimental
inflammation. Clinically, of the previously known
NMDA antagonists
amantadine,
dextromethorphan and
ketamine have been tested, the latter extensively.
Ketamine has been found quite active in certain cases of
neuropathic pain and it reduced the
opiate demand when used for postoperative
analgesia. However, in other types of clinical
pain their efficacy is less convincing. Not being registered there are no clinical data on the
AMPA antagonists. There are, however, some
investigational new drugs and some novel compounds in the stage of preclinical development which antagonise the
AMPA receptors in competitive fashion or allosterically. Of the latter molecules 2,3-benzodiazepines are particularly promising.