Low dose ketamine: a therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways

Ketamine is a dissociative anaesthetic that has been used in the clinic for many years. At low, subanaesthetic doses, it is a relatively selective and potent antagonist of the N-methyl-D-aspartate (NMDA) receptor. It belongs to the class of uncompetitive antagonists and blocks the receptor by binding to a specific site within the NMDA receptor channel when it is open. Like other compounds of this class, ketamine can cause hallucinations or other untoward central effects which limit its use in the clinic. Nevertheless, because of the evidence on the importance of NMDA receptor-mediated pLasticity in chronic pain, low doses of ketamine have been explored in a wide range of pain conditions. The majority of studies with ketamine have shown efficacy; however, it has not been possible to separate safely the pain relief from the side effects of the drug. Hence, clinical use of ketamine as a pain treatment is very limited. Nevertheless, ketamine has served as a useful tool to provide a compelling rationale for developing other NMDA antagonists. Some of the new compounds of this class, particularly those acting at the NR2B subtype of the NMDA receptor, have shown promise in preclinical and clinical studies.