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アドレナリンα2A受容体サブタイプに対するα2作動薬の作用に関する研究
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| Title: | アドレナリンα2A受容体サブタイプに対するα2作動薬の作用に関する研究 |
| Other Titles: | Potential actions of α2 adrenoceptor agonists on α2A adrenoceptor subtype. |
| Authors: | 小林, 武志1 Browse this author |
| Authors(alt): | Kobayashi, Takeshi1 |
| Issue Date: | 23-Mar-2017 |
| Publisher: | Hokkaido University |
| Abstract: | α2-Adrenoceptor (AR) agonists, dexmedetomidine (DEX) and xylazine (XYL), are clinically used for sedation and analgesia in humans and animals. The effect of xylazine shows marked species difference. α2A-AR subtype is reported to be important for the effect of α2-AR agonist, but precise mechanism of action of α2-AR agonists is still unclear.
In the chapter I, the effect of DEX and XYL by using functional α2A-AR KO mice (D79N) was estimated. In the isolated spinal cord preparation of mice, DEX and XYL inhibited both slow ventral root potential (sVRP), which is thought to reflect a nociceptive pathway, and monosynaptic reflex potential (MSR). sVRP was more sensitive to these agonists than MSR. sVRP inhibitions by DEX and XYL were attenuated in D79N mice. sVRP inhibition by DEX in D79N mice was reversed by atipamezole (α2-AR antagonist), but not by JP1302 (α2C-AR antagonist), efaroxan (imidazoline I1 receptor antagonist) nor idazoxan (I2 antagonist). sVRP inhibition by XYL in D79N mice was not reversed by atipamezole, JP1302, efaroxan nor idazoxan. XYL but not DEX suppressed the conduction of compound action potential in the spinal nerves. In vivo analgesic effect of DEX and XYL were not observed in D79N mice.
In the chapter II, in silico docking of α2A-AR and DEX or XYL was simulated. The binding pocket of DEX was located in transmembrane (TM) 356 region of mouse, bovine α2A-AR and in TM56 region of swine α2A-AR. In both cases, DEX potently bound with Tyr residue of TM5. In mouse and bovine α2A-AR, the binding pocket of XYL was located in TM56 region, while, in swine α2A-AR, the binding pocket was located in TM345 region. Exchange of 3rd intracellular loop domain between mouse and swine α2A-AR altered the region and stability of binding pocket of XYL.
These results indicate that α2A-AR plays an important role in sVRP inhibition and analgesic effects by DEX and XYL. XYL also inhibits conduction of action potential at its high concentrations, which is not mediated by α2A-AR. Swine α2A-AR has a unique binding pocket for XYL, which may be determined by the 3rd intracellular loop domain. The species difference in the analgesic effect of XYL could be due to the variation in the binding pocket in α2A-AR. |
| Conffering University: | 北海道大学 |
| Degree Report Number: | 甲第12616号 |
| Degree Level: | 博士 |
| Degree Discipline: | 獣医学 |
| Examination Committee Members: | (主査) 准教授 乙黒 兼一, 教授 木村 和弘, 教授 石塚 真由美, 名誉教授 伊藤 茂男 |
| Degree Affiliation: | 獣医学研究科（獣医学専攻） |
| Type: | theses (doctoral) |
| URI: | http://hdl.handle.net/2115/72906 |
| Appears in Collections: | 課程博士 (Doctorate by way of Advanced Course) > 獣医学院(Graduate School of Veterinary Medicine)
学位論文 (Theses) > 博士 （獣医学）
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