Interaction of the Chiral Forms of Ketamine with Opioid, Phencyclidine, σ and Muscarinic Receptors

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Abstract
In order to elucidate the mechanisms of action of ketamine, we have investigated the binding of the chiral forms of ketamine to opioid (μ, δ and κ), phencyclidine, σ and muscarinic receptors and we have performed detailed concentration‐response experiments in the guinea‐pig ileum preparation. The affinity ratios for the chiral forms at phencyclidine, μ and κ receptors correlated with the potency ratio of the chiral forms in the ischaemic pain test found previously. The affinities were highest for phencyclidine receptors. The affinities for muscarinic receptors were lower than for phencyclidine receptors by a factor of about 10–20. The concentration‐response experiments revealed one opioid (naloxone sensitive) and one non‐opioid component. The two component are very close, which explains why other authors have reported that naloxone antagonizes the ketamine effect only partly. The concentrations of naloxone necessary to shift the opioid part of the curves indicate that ketamine is a κ agonist in the guinea‐pig ileum preparation. We conclude that the analgesic effect of ketamine in humans is most probably mediated via phencyclidine receptors, although a κ effect can not be excluded. Binding to κ and muscarinic receptors may contribute to the psychotomimetic side effects seen during recovery from ketamine anaesthesia.