A. Donald Finck

Opiate Receptor Mediation of Ketamine Analgesia

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 (witch-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.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

Prolonged Exposure to Nitrous Oxide Decreases Opiate Receptor Density in Rat Brainstem

Groups of rats were exposed to air or 80 per cent nitrous oxide for 30 min or 18 h, following which the brainstem opiate receptor density and the apparent affinity of these receptors to the radiolabeled agonist, 3H-dihydromorphine, were assayed. Thirty-minute exposure to nitrous oxide did not change opiate receptor characteristics, immediately or 17.5 h later. However, prolonged exposure to nitrous oxide (18 h) decreased the brainstem opiate receptor density approximately 20 per cent, without a change in apparent receptor affinity. These results support the view that nitrous-oxide-induced analgesia results from release of endogenous opiate-like substances. Continued presence of these substances in turn results in a decrease in opiate receptor density and may account for the development of tolerance to the analgesic action of nitrous oxide.

Tolerance to nitrous oxide analgesia in rats and mice.

The purpose of these experiments was to characterize the nature of tolerance to the analgesic action of nitrous oxide. Analgesia was assessed in rats using a tail-flick latency test and in mice using an abdominal constriction test. Rats and mice were exposed to nitrous oxide, 75 per cent, the balance oxygen, continuously for 16–18 hours. On re-exposure to nitrous oxide 30 min later, these animals were found tolerant to nitrous oxide in that the analgesic response was decreased by at least 50 per cent. Animals folerant to nitrous oxide were not tolerant to morphine. Morphine (0.25–1.5 mg/kg) produced equal degrees of analgesia in control and nitrous oxide-tolerant mice and rats. In contrast, rats made tolerant to morphine by repeated daily injections of as much as 400 mg/kg subcutaneously or by subcutaneous implantation of morphine pellets (75 mg, twice) showed a decreased analgesic response to nitrous oxide. Thus the cross-tolerance between nitrous oxide and morphine appears unique in that it is unidirectional.

Acetylcholine concentrations and turnover in rat brain structures during anesthesia with halothane, enflurane, and ketamine.

Acetylcholine and choline concentrations in brain structures of rats during anesthesia with halothane (0.7-1.0 per cent inspired), enflurane (2.7-3.0 per cent, inspired) and ketamine (40 mg/kg, iv) were measured by gas chromatography. The turnover rate (biosynthesis) of acetylcholine in vivo was estimated by infusing phosphoryl(Me-14C)choline intravenously, determining specific activities of choline and acetylcholine, and applying principles of steady-state kinetics to compute the fractional rate constant of acetylcholine. Acetylcholine concentrations in brain structures did not change during anesthesia. Halothane decreased the acetylcholine turnover rates in all parts of the brain. Enflurane decreased the acetylcholine turnover rate in the cerebral cortex only, but not in the caudate nucleus, the hippocampus, and the hypothalamic and thalamic regions. During anesthesia with ketamine, acetylcholine turnover rates were reduced in the caudate nucleus and the hippocampus, but not in the cerebral cortex and the hypothalamic and thalamic regions. The results suggest that acetylcholine turnover rate and utilization are related to anesthetic-induced electrophysiologic changes in cortical and subcortical structures.

Morphine Tolerance Decreases the Analgesic Effects of Ketamine in Mice

Previous studies have shown that ketamine interacts with opiate receptors, and it has been suggested that ketamine-induced analgesia is mediated through opiate receptors. If so, ketamine should produce less analgesia in morphine tolerant animals, just as morphine does. To test this hypothesis, the analgesic effects of ketamine were tested in mice implanted with placebo pellets and in mice made tolerant to morphine through implantation of morphine pellets, using the abdominal constriction test. The test consisted of ip injection of 1% acetic acid, which caused stretching of hind limbs and constriction of abdominal muscles, also called writhing. The number of writhes was counted for each mouse 10–15 min following acetic acid injection. Morphine pellet implanted mice treated with saline writhed 12.2 ± 0.8 times (mean ± SEM), not significantly different from 9.8 ± 0.9 times seen in placebo pellet implanted mice. Treatment of the animals with ketamine at three doses of 20, 25, and 30 mg/kg, subcutaneously (sc), reduced the number of writhes in the placebo pellet implanted group to 5.8 ± 0.8, 4.2 ± 0.7, and 1.3 ± 0.3, respectively. In the morphine pellet-implanted group, with the same doses of ketamine, the numbers of writhes were 10 ± 0.9, 9.3 ± 1.1, and 5.2 ± 0.9, respectively. Morphine-tolerant animals writhed significantly more at each dose of ketamine, indicating that they were cross tolerant to the analgesic effects of ketamine.