The mechanisms of analgesic effects of Tramadol and Alphaxalone

曲马多和 Alphaxalone 的镇痛作用机制

• 批准号: 13671626
• 负责人: SHIGEMATSU Akio
• 金额: $ 2.18万
• 依托单位: University of Occupational Environmental Health (UOEH)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671626/
• 关键词: neurosteroid anestheticis; tramadol; alphaxalone; norepinephrine transporter; nicotinic acetylcholine receptor; Xenopus oocytes; adrenal medullary cells; muscarinic receptor; ニコチン性アセチルコリン受容体イオンチャネル; ノルアドレナリントランスポーター; 腎血流

The mode of action of the analgesic tramadol and alphaxalone, a neurosteroid anestheticis not well understood.We assayed the effect of tramadol and alphaxalone on [^3H]-norepinephrine ([^3H]-NE) uptake and [^3H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We also investigated the effects of tramadol and alphaxalone on muscarinic receptors type 1 and 3, using a Xenopus oocyte expression system. Finally, we investigated the effect of tramadol and alphaxalone on catecholamine secretion, nicotine-induced calcium rises and inward currents using a Ca^<2+>-imaging system and the whole-cell patch clamp technique in bovine adrenal chromaffin cells.(1) Both tramadol and alphaxalone competitively inhibited norepinephrine transporter function at desipramine binding sites.(2) Both tramadol and alphaxalone at clinically relevant concentrations inhibits m1 and m3 function via QNB-binding sites.(3) Tramadol and alphaxalone inhibits catecholamine secretion by inhibiting nicotinic acetylcholine receptor functions and suggest that such inhibitory effects could be one of the antinociceptive mechanisms exerted by tramadol.

镇痛药曲马多和神经类固醇麻醉药阿尔法沙龙的作用方式尚不清楚。研究了曲马多和阿霉素对[^3H]-去甲肾上腺素（[^3H]-NE）摄取和[^3H]-去西帕胺与牛肾上腺髓质分离质膜结合的影响。我们还利用非洲爪蟾卵细胞表达系统研究了曲马多和阿霉素对毒蕈碱受体1型和3型的影响。最后，我们利用Ca^<2+>-成像系统和全细胞膜片钳技术研究了曲马多和阿霉素对牛肾上腺染色质细胞儿茶酚胺分泌、尼古丁诱导的钙升高和内向电流的影响。(1)曲马多和阿霉素竞争性地抑制去西帕明结合位点的去甲肾上腺素转运蛋白功能。(2)曲马多和阿霉素在临床相关浓度下均可通过qnb结合位点抑制m1和m3功能。(3)曲马多和阿霉素通过抑制烟碱乙酰胆碱受体功能抑制儿茶酚胺分泌，提示这种抑制作用可能是曲马多抗伤害感受作用的机制之一。

项目成果

Sagata K: "Tramadol inhibits nor epinephrine transporter function at desipramine binding sites in cultured bovine adrenal medullary cells"Anesth Analg. (In Press).

Sagata K：“曲马多在培养的牛肾上腺髓质细胞中的地昔帕明结合位点上抑制肾上腺素转运蛋白功能”Anesth Analg。

Horishita T: "Alphaxalone, a neurosteroid anesthetic, inhibits norepinephrine transporter function in cultured bovine adrenal medullary cells"Anesth Analg. 95・6. 1661-1666 (2002)

Horishita T：“Alphaxalone，一种神经类固醇麻醉剂，抑制培养的牛肾上腺髓质细胞中的去甲肾上腺素转运蛋白功能”Anesth Analg 95·6（2002）。

Sagata K., et al.: "Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells"Anesth Analg.. 94-2. 901-906 (2002)

Sagata K.等人：“曲马多抑制培养的牛肾上腺髓质细胞中地昔帕明结合位点的去甲肾上腺素转运蛋白功能”Anesth Analg.. 94-2。

Shiraishi M., et al.: "Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors"J Pharmacol Exp Ther.. 299-1. 255-260 (2001)

Shiraishi M. 等人：“在培养的肾上腺髓质细胞和表达克隆 M1 受体的非洲爪蟾卵母细胞中，曲马多对毒蕈碱受体诱导的反应的抑制”J Pharmacol Exp Ther. 299-1。

Shiraishi M: "Inhibitory effects of tramadol on nicotinic acetyicholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha7 receptors"Br J Pharmacol. 136・2. 207-216 (2002)

白石 M：“曲马多对肾上腺嗜铬细胞和表达 α7 受体的非洲爪蟾卵母细胞的抑制作用”Br J Pharmacol 136·2 (2002)。