Evidence of a role for NMDA receptors in pain perception.
Both chiral forms of ketamine caused analgesia when administered in subanesthetic doses to human volunteers suffering acute, experimentally induced ischemic pain. S-Ketamine was 4 times more potent than R-ketamine as an analgesic agent in this model system. The relative order of analgesic potency of the two enantiomers was compared to their relative affinity for phencyclidine (PCP) binding sites (associated with the NMDA receptor-operated ion channel) and for sigma binding sites (which are not associated with the NMDA receptor complex). The relative analgesic potency of the enantiomers correlated positively with their relative affinity for PCP sites and negatively with their relative affinity for sigma sites. The results strongly indicate that PCP sites, but not sigma sites, are functional receptors mediating the analgesic effect of ketamine. This is consistent with the hypothesis that NMDA receptors are essential for pain perception in humans. Disturbances of other sensory modalities, in particular somatosensory perception, vision and hearing, were the main side-effects observed. These effects were qualitatively similar for both enantiomers and were closely associated with their analgesic action. The NMDA type of excitatory amino acid receptor thus appears to be widely involved in the processing of sensory afferent signals in the human brain.
Klepstad
P
P
Department of Pharmacology, Oslo University School of Medicine, Norway.
Maurset
A
A
Moberg
E R
ER
Oye
I
I
D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D017465:Receptors, Opioid, delta; D017478:Receptors, Phencyclidine; D013237:Stereoisomerism
D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017478:Receptors, Phencyclidine; D007649:Ketamine; C012058:tenocyclidine; D010622:Phencyclidine