[Mechanisms of action of ketamine]

Although ketamine has been in clinical use for 3 decades, the neuropharmacological basis of its analgesic, anaesthetic, sympathomimetic, and psychotomimetic effects is still a subject of controversial discussion and intensive investigational efforts. In recent years, however, new experimental approaches to its effects on the cellular and molecular level and the availability of pure ketamine enantiomers contributed substantially to the understanding of its complex neuropharmacology. This article reviews the current knowledge of ketamine effects on ligand-operated and voltage-operated transmembrane ion channels, G-protein-coupled receptors, transmitter uptake, and the NO-cGMP system in neurons. With regard to its potential clinical relevance and supposed relative role among the complex mechanisms involved in pain perception, analgesia, anaesthesia, and psychotomimesis, the contributions of recent experimental and clinical findings to the identification of major target sites of ketamine are summarised. In contrast to the uncertainty surrounding the potential role of opioid receptors, there is now considerable evidence that NMDA antagonism is a central mechanism that contributes to the amnesic, analgesic, anaesthetic, and psychotomimetic as well as the neuroprotective actions of ketamine. Moreover, the involvement of non-NMDA glutamate receptors, muscarinic and nicotinic cholinergic transmission, interactions with 5-HT receptors, and L-Type Ca2+ channels may account for some of its anaesthetic and neuroprotective properties.