Global Preclinical Research and Development, Department of Pharmacology, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany.
J Pharmacol Exp Ther. 2011 Apr;337(1):312-20. doi: 10.1124/jpet.110.175042. Epub 2011 Jan 24.
The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α(2)-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action.
新型中枢作用镇痛药酒石酸布托啡诺[（-）-（1R，2R）-3-（3-二甲氨基-1-乙基-2-甲基丙基）-苯酚盐酸盐]在一个分子中结合了两种作用机制，即μ-阿片受体（MOR）激动剂和去甲肾上腺素再摄取抑制剂（NRI）。药理学拮抗研究表明，两种作用机制都有助于布托啡诺的镇痛作用。本研究旨在探讨两种机制相互作用的性质。在大鼠中单独给予布托啡诺或与阿片拮抗剂纳洛酮或α（2）-肾上腺素能受体拮抗剂育亨宾联合给药，生成剂量-反应曲线。使用了两种不同的疼痛模型：1）低强度尾部闪烁和 2）脊神经结扎。在每个模型中，我们获得了剂量-效应关系，以揭示基于 MOR 激动剂、NRI 和未阻断布托啡诺的布托啡诺的作用。受体分数占有率是根据布托啡诺的脑浓度及其对每个结合位点的解离常数确定的。布托啡诺在两种疼痛模型中均产生剂量依赖性镇痛作用，两种拮抗剂均使布托啡诺的剂量-效应曲线向右移位，从而提供了区分 MOR 激动剂和 NRI 的数据。占据效应数据的同量线分析和从效应尺度确定相互作用的理论等效方法均表明，布托啡诺的两种作用机制之间存在非常明显的协同相互作用。这可能解释了为什么尽管布托啡诺对 MOR 的亲和力低 50 倍，但在各种临床前疼痛模型中，其效力仅为吗啡的 2 至 3 倍。这可能是首次证明具有两种作用机制的单一化合物的受体占有率具有协同相互作用。
