European Journal of Pharmacology, 61 (1980) 389--391 © Elsevier/North-Holland Biomedical Press Short communication FAILURE OF KETAMINE TO INTERACT WITH OPIATE RECEPTORS WALTER FRATTA, MARIANO CASU, ANGELO BALESTRIERI *, ANDREA LOVISELLI *, GIOVANNI BIGGIO and GIAN LUIGI GESSA Institutes of Pharmacology and * Medical Pathology 3rd, University of Cagliari, Cagliari, Italy Received 30 October 1979, accepted 19 December 1979 389 W. FRATTA, M. CASU, A. BALESTRIERI, A. LOVISELLI, G. BIGGIO and G.L. GESSA, Failure ofketamine to interact with opiate receptors, European J. Pharmacol. 61 (1980) 389--391. Ketamine, an anesthetic agent endowed with several morphine-like effects, failed to displace 3H-dihydro- morphine or 3H-methionine-enkephalin from opiate receptors in the rat brain synaptosomal-mitochondrial mem- brane preparations. Furthermore, ketamine-induced analgesia in rats was not antagonized by naloxone, suggesting that this effect is not mediated by opiate receptors. Ketamine Methionine-enkephalin Morphine Naloxone Opiate receptors 1. Introduction Ketamine (d,l-2-(o-chlorophenyl)-2(methyl- aminocyclohexanone) is a widely used anes- thetic agent. Besides the production of the so-called dissociative anesthesia, ketamine may cause post-anesthetic mood changes, hallu- cination and confusion (Garfield et al., 1972}. Moreover, ketamine, like morphine, has the capability to induce analgesia in both animals and humans (Bovill et al., 1971), to increase motor activity (Myslobodsky et al., 1979) and to modify serotonin (Vargiu et al., 1978) and dopamine synthesis in rodents (Sung et al., 1973; Ylitalo et al., 1976). Recent uncon- trolled studies (A. Pesce, S. Giovanni Hospital, Rome, Italy. Personal Communication) have suggested that ketamine may be useful in the maintenance therapy of heroin addcits. These findings prompted us to clarify whether ketamine might interact with opiate receptors and test if ketamine-induced anal- gesia was antagonized by naloxone, a narcotic antagonist. 2. Materials and methods Male Sprague-Dawley CD rats (Charles River, Como, Iraly) weighing 200-230 g were decapitated and the brains removed imme- diately. The cerebellum, which contains negligible binding (Pert and Snyder, 1973}, was excised and the remainder of the brain was placed immediately in the appropriate volume of iced Tris HC1 buffer (50 raM, pH 7.7) and homogenized with a Brinkmann Politron. Specific dihydromorphine receptor binding assay was carried out at 25°C in freshly prepared crude synaptosomal-mito- chondrial membrane preparations in the presence of 3H<lihydromorphine concentra- tions ranging from 0.1 to 8 nM using 300 #g membrane proteins. Specific methionine- enkephalin receptor binding assay was carried out at 0°C in freshly prepared crude synapto- somal-mitochondrial membrane preparations in the presence of 3H-methionine-enkephalin concentrations ranging from 0.25 to 14 nM using 600 pg membrane proteins.