| Co-Investigator(Kenkyū-buntansha) |
MINAMI Kouichiro Jichi Medical School, Department of Anesthesiology, Assistant Professor (70279347)
UETA Yoichi University of Occupational&Environmental Health, Japan, School of Medicine, Professor (10232745)
ATUSHI Takizuka University of Occupational&Environmental Health, Japan, School of Medicine, Research Associate (00399205)
SHIRAISHI Munehiro University of Occupational&Environmental Health, Japan, School of Medicine, Research Associate (40389458)
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| Budget Amount *help |
¥3,740,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2006: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
Dexmedetomidine, an alpha (2)-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 alpha (2)-adrenoceptor. We examined the effects of dexmedetomidine on M (1), M (3), 5-HT (2C), 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[Ca (2+)] (i) in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT (2C)-, 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 microM)-induced Ca (2+)-activated Cl (-) currents in Xenopus oocytes expressing M (1) receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M (3) receptors; 1nM, 10nM, 100nM, and 1microM 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 (EC (50)=3.5+/-0.7nM). 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[Ca (2+)] (i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M (3) receptors, in addition to its agonistic effects on alpha (2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.
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