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Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors.

O Hustveit, A Maurset, I Oye

Pharmacology & Toxicology December 1, 1995 DOI: 10.1111/j.1600-0773.1995.tb01041.x (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics In vitro binding and concentration-response study Peer reviewed
Population Guinea-pig ileum preparations
Intervention Ketamine
Topics Ketamine Esketamine
Keywords Ileum Animals Guinea pigs Receptors, muscarinic Receptors, opioid Receptors, phencyclidine Anesthetics, intravenous Anesthetics, dissociative Radioligand assay Binding sites Muscle contraction Dose-response relationship, drug Drug interactions Stereoisomerism Male In vitro techniques
Key points The authors conclude that ketamine's analgesic effect in humans is most probably mediated via phencyclidine receptors, although a kappa effect cannot be excluded. Affinities were highest at phencyclidine receptors, with muscarinic affinities about 10-20 times lower, and the guinea-pig ileum response had a naloxone-sensitive opioid component and a non-opioid component that were very close together.

Abstract

In order to elucidate the mechanisms of action of ketamine, we have investigated the binding of the chiral forms of ketamine to opioid (mu, delta and kappa), phencyclidine, sigma 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, mu and kappa 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 kappa 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 kappa effect can not be excluded. Binding to kappa and muscarinic receptors may contribute to the psychotomimetic side effects seen during recovery from ketamine anaesthesia.

Comparable studies

Other preclinical and animal studies on ketamine, most cited first.

Study Year Design Participants
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats 2010 Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats 1997 Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice 2016 Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats 1983 Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice 2015 Experimental study

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