Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells

Dexmedetomidine, an α2-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the α2-adrenoceptor. We examined the effects of dexmedetomidine on M1, M3, 5-HT2C, substance P, and orexin 1 receptors in Xenopus oocytes expressing individual receptors. In addition, we investigated the effects of dexmedetomidine on muscarinic receptor-mediated changes in [Ca2+]i in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT2C-, or substance P-induced Cl− currents and had little inhibition on the orexin A-induced current in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1 μM)-induced Ca2+-activated Cl− currents in Xenopus oocytes expressing M1 receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M3 receptors; 1 nM, 10 nM, 100 nM, and 1 μM dexmedetomidine reduced the current to 66.5 ± 4.8, 51.3 ± 12, 34.6 ± 11, and 26.8 ± 6.4% of the control value, respectively (EC50 = 3.5 ± 0.7 nM). Dexmedetomidine reduced the ACh-induced Cl− currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca2+]i in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M3 receptors, in addition to its agonistic effects on α2-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.