Grünenthal GmbH, Global Preclinical Research and Development, Department of Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany.
Neurosci Lett. 2011 Mar 17;491(2):104-7. doi: 10.1016/j.neulet.2011.01.014. Epub 2011 Jan 11.
Activation of the μ-opioid receptor (MOR) and noradrenaline reuptake inhibition (NRI) are well recognized as analgesic principles in acute and chronic pain indications. The novel analgesic tapentadol combines MOR agonism and NRI in a single molecule. The present study used OPRM1 (MOR) knockout (KO) mice to determine the relative contribution of MOR activation to tapentadol-induced analgesia in models of acute (nociceptive) and chronic (neuropathic) pain. Antinociceptive efficacy was inferred from paw withdrawal latencies on a 48 °C hot plate in naive animals. Antihyperalgesic efficacy was inferred from the number of nocifensive reactions in diabetic animals (streptozotocin-induced) and non-diabetic controls on a 50 °C hot plate. The effect of tapentadol (0.316-31.6 mg/kg IP) and the MOR agonist morphine (3-10 mg/kg IP) was determined in OPRM1 KO- and congenic wildtype mice. At baseline, diabetic OPRM1 KO mice showed reduced nocifensive reactions as compared to diabetic wildtype mice. In both pain models, morphine and tapentadol were effective in wildtype mice. In the KO mice, however, morphine failed to produce analgesia in either model. On the other hand, tapentadol still had clear effects, and when tested at a dose that was fully efficacious in wildtype mice, showed reduced but still significant antinociceptive efficacy in non-diabetic, and antihyperalgesic efficacy in diabetic OPRM1 KO mice. The remaining antinociceptive activity of tapentadol in OPRM1 KO mice was abolished by the α₂-adrenoceptor antagonist yohimbine. In OPRM1 wildtype mice, the antihyperalgesic effect of tapentadol was 10 times more potent in diabetic animals (ED₅₀=1.10 mg/kg) than its antinociceptive effect in naïve animals (ED₅₀=10.8 mg/kg). This study supports the conclusion that the analgesic effect of tapentadol is only partly due to the activation of MOR, both under acute and chronic pain conditions, and that the efficacy of tapentadol against acute and chronic pain is based on its combined mechanism of action.
μ-阿片受体（MOR）的激活和去甲肾上腺素再摄取抑制（NRI）在急性和慢性疼痛适应症中被公认为镇痛原理。新型镇痛药曲马多在单一分子中结合了MOR激动作用和NRI。本研究使用OPRM1（MOR）基因敲除（KO）小鼠来确定在急性（伤害性）和慢性（神经性）疼痛模型中，MOR激活对曲马多诱导的镇痛作用的相对贡献。通过未处理动物在48°C热板上的爪退缩潜伏期推断抗伤害感受效能。通过糖尿病动物（链脲佐菌素诱导）和非糖尿病对照在50°C热板上的伤害性反应数量推断抗痛觉过敏效能。在OPRM1基因敲除小鼠和同基因野生型小鼠中测定了曲马多（0.316 - 31.6mg/kg腹腔注射）和MOR激动剂吗啡（3 - 10mg/kg腹腔注射）的作用。在基线时，糖尿病OPRM1基因敲除小鼠与糖尿病野生型小鼠相比，伤害性反应减少。在两种疼痛模型中，吗啡和曲马多在野生型小鼠中均有效。然而，在基因敲除小鼠中，吗啡在两种模型中均未能产生镇痛作用。另一方面，曲马多仍有明显作用，当以在野生型小鼠中完全有效的剂量进行测试时，在非糖尿病OPRM1基因敲除小鼠中显示出降低但仍显著的抗伤害感受效能，在糖尿病OPRM1基因敲除小鼠中显示出抗痛觉过敏效能。曲马多在OPRM1基因敲除小鼠中剩余的抗伤害感受活性被α₂-肾上腺素能受体拮抗剂育亨宾消除。在OPRM1野生型小鼠中，曲马多在糖尿病动物中的抗痛觉过敏作用（ED₅₀ = 1.10mg/kg）比其在未处理动物中的抗伤害感受作用（ED₅₀ = 10.8mg/kg）强10倍。本研究支持以下结论：在急性和慢性疼痛条件下，曲马多的镇痛作用仅部分归因于MOR的激活，并且曲马多对急性和慢性疼痛的疗效基于其联合作用机制。
