Opiate Receptor Mediation of Ketamine Analgesia

TLDR

Ketamine analgesia can be antagonized by the narcotic antagonist naloxone. The authors investigated ketamine’s similarity to narcotics by testing its effects in three standard opiate receptor assays. Ketamine binds stereospecifically to opiate receptors, with (+) ketamine 2–3 times more potent than (−), inhibits guinea pig ileum contractions partially blocked by naloxone, displaces 3H‑etorphine in thalamic but not cortical mouse brain, indicating that opiate receptors mediate a significant portion of its analgesic effect.

Abstract

Previous workers have noted that analgesia produced by ketamine can be antagonized by the narcotic antagonist, naloxone. In order to elaborate further the apparent similarity between ketamine- and narcotic-induced analgesia, the authors examined the effects of ketamine in three standard test systems for the opiate receptor. In a radioligand binding assay using 3H-dihydromorphine, ketamine stereospecifically bound to opiate receptors in rat brain homogenate, (+) ketamine being 2-3 times more potent than the (-) enantiomer of ketamine. In a bioassay for the opiate receptor, using the longitudinal muscle-myenteric plexus of the guinea pig ileum, ketamine inhibited the twitch-like muscular contractions, as do narcotics. However, only the inhibitory effects of (+) ketamine, which in this system also was twice as potent as (-) ketamine, could be partially antagonized by naloxone, suggesting that this enantiomer is responsible for the opiate receptor-related effects of ketamine. In vivo, the authors found that ketamine displaces 3H-etorphine, a potent narcotic, from opiate receptors in regional areas of the mouse brain, especially in the thalamic region, but not in the cortex. The results suggest that a significant mechanism of ketamine-induced analgesia is mediated by opiate receptors.