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Background: The aim of this study was to determine the effects of different concentrations of muscone on the ketamine requirement for hypnosis and analgesia and possible mechanism in mice. Methods: In the hypnotic response experiment, muscone (0.5, 1.0, 2.0, 4.0, and 8.0 mg/kg) was administered 15 minutes before ketamine by intraperitoneal injection. The hypnotic response was evaluated by loss of righting reflex (LORR). In the analgesia experiment, muscone (0.5, 1.0, 2.0, and 4.0 mg/kg) was administered 15 minutes before 50 mg/kg ketamine injection. Pain threshold was assessed by measuring the tail-flick latency induced by heat radiation. Twenty minutes after ketamine injection, the mRNA expression of N-methyl-d-aspartate receptors (NR) subunits, γ-aminobutyric acid (GABA) receptors subunits, opioid receptors subunits, and some Na+ and Ca2+ channels were detected by qPCR in the hippocampus of mice. Results: The 50% effective dose (ED50) with 95% confidence interval of ketamine-induced LORR was 49.2 (43.4-56.4) mg/kg. About 4.0 or 8.0 mg/kg muscone increased ED50 of ketamine-induced hypnosis, which was 82.7 (70.0-98.4) mg/kg or 72.0 (65.4- 85.7) mg/kg, respectively. In the analgesic experiment, ketamine alone caused an obvious analgesic effect, whereas different dose of muscone decreased pain threshold in the presence of ketamine; 4.0 mg/kg muscone up-regulated the mRNA expression of NR1 and inhibited ketamine-induced increase of δ-opioid receptor mRNA level. Muscone also inhibited Cav2.1 mRNA expression in the presence of ketamine. Conclusion: Muscone reduced the hypnotic and analgesic effect of ketamine in dose-independent manner in mice, which may be related to the changes of NR1 and δ-opioid receptor. [ABSTRACT FROM AUTHOR]