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

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Abstract

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.

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Authors and Affiliations

  1. Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan

    Atsushi Takizuka, Takafumi Horishita & Munehiro Shiraishi

  2. Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotuke, Tochigi, 329-0428, Japan

    Kouichiro Minami

  3. Emergency Life-Saving Technique Academy of Tokyo (ELSTA TOKYO), 4-5 Minamiosawa, Hachioji, Tokyo, 192-0364, Japan

    Kouichiro Minami

  4. Department of Physiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan

    Kouichiro Minami, Toru Yokoyama & Yoichi Ueta

  5. Department of Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Yasuhito Uezono

  6. Department of Molecular Pharmacology, Graduation School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8575, Japan

    Takeshi Sakurai

  7. School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan

    Akio Shigematsu

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  1. Atsushi Takizuka
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Correspondence to Kouichiro Minami.

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Takizuka, A., Minami, K., Uezono, Y. et al. Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells. Naunyn-Schmied Arch Pharmacol 375, 293–301 (2007). https://doi.org/10.1007/s00210-007-0168-4

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  • DOI: https://doi.org/10.1007/s00210-007-0168-4

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