The mechanisms of analgesic effects of Tramadol and Alphaxalone

镇痛药曲马多和神经甾体麻醉药阿法沙龙的作用机制尚不清楚，我们测定了曲马多和阿法沙龙对[^3H]-去甲肾上腺素（[^3H]-NE）摄取和[^3H]-去甲丙咪嗪与牛肾上腺髓质质膜结合的影响。我们还研究了曲马多和阿法沙龙对毒蕈碱受体1型和3型的影响，使用非洲爪蟾卵母细胞表达系统。最后，我们在牛肾上腺嗜铬细胞上用Ca^<2+>成像系统和全细胞膜片钳技术研究了曲马多和阿法沙龙对儿茶酚胺分泌、尼古丁诱导的钙升高和内向电流的影响。(1)曲马多和阿法沙龙都竞争性抑制去甲肾上腺素转运蛋白在地昔帕明结合位点的功能。(2)临床相关浓度的曲马多和阿法沙龙均通过QNB结合位点抑制M1和M3功能。(3)曲马多和阿法沙龙通过抑制烟碱乙酰胆碱受体功能抑制儿茶酚胺分泌，表明这种抑制作用可能是曲马多产生的抗伤害性感受机制之一。

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.