Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine

Abstract

Ketamine is a racemic mixture of equal amounts of R-ketamine and S-ketamine and is well known to anesthesiologists for its unique dissociative anesthetic properties. The pharmacological properties of ketamine, namely, its sympathetic excitation, mild respiratory depression, and potent analgesia, are still highly valued in its use as an anesthetic for some patients. In particular, since its advent, S-ketamine has been widely used as an anesthetic in many countries due to its increased affinity for NMDA receptors and its enhanced anesthetic and analgesic effects. However, the anesthetic and analgesic mechanisms of S-ketamine are not fully understood. In addition to antagonizing NMDA receptors, a variety of other receptors or channels may be involved, but there are no relevant mechanistic summaries in the literature. Therefore, the purpose of this paper is to review the mechanisms of action of S-ketamine on relevant receptors and systems in the body that result in its pharmacological properties, such as anesthesia and analgesia, with the aim of providing a reference for its clinical applications and research.

Keywords: AMPA; NMDA; S-ketamine; analgesia; anesthesia; ketamine; opioid receptor.

FIGURE 1

Domain organization of NMDA receptor subunits. The GluN1-GluN2A heterodimer is shown on the left, and the GluN1-GluN2B heterodimer is shown on the right. Blue indicates the GluN1 subunit, purple indicates the GluN2A subunit, yellow indicates the GluN2B subunit, and the green receptor indicated by the dotted line is the binding site of S-ketamine.

FIGURE 2

Schematic diagram of NMDA receptor structure. The green receptor indicated by the dotted line is the binding site of S-ketamine. The three PDZ structural domains linked below the GluN2B subunit form PSD-95, which can interact with nNOS to regulate the production of NO.

FIGURE 3

Simple diagram of S-ketamine producing anesthesia and analgesia. S-ketamine acts on GluN1-GluN2A and GluN1-GluN2B subunits and blocks NMDA receptor channels, which is the basis of S-ketamine-induced loss of consciousness and analgesia. Moreover, inhibition of presynaptic NMDA receptor channels can lead to deinhibition of glutamatergic neuronal activity and indirect activation of AMPA receptors.

FIGURE 4

S-Ketamine produces analgesia by other pathways. S-ketamine excites sympathetic nerves, leading to the release of NA. NA both activates the descending analgesic pathway, which produces analgesic effects, and binds to adrenoceptors (ARs), promoting the release of opioids (OPs) from immune cells. Both S-ketamine and OP can bind to the opioid receptor (OR), decreasing intracellular cAMP levels and thus blocking Ca²⁺ channels and TRPV1 channels to produce an analgesic effect.