Benoist Jean-Michel, Keime Florence, Montagne Jacqueline, Noble Florence, Fournié-Zaluski Marie-Claude, Roques Bernard P, Willer Jean-Claude, Le Bars Daniel
Laboratoire de Physiopharmacologie du Système nerveux, INSERM U161, 2 rue d'Alésia, 75014 Paris Cedex, France.
Eur J Pharmacol. 2002 Jun 12;445(3):201-10. doi: 10.1016/s0014-2999(02)01753-3.
The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.
脑啡肽降解酶中性内肽酶和氨肽酶N的双重抑制剂N-[(R,S)-2-苄基-3[(S)-(2-氨基-4-甲硫基)丁基二硫醇]-1-氧代丙基]-L-苯丙氨酸苄酯（RB101）对麻醉大鼠腓肠神经区域电刺激诱发的C纤维反射的作用进行了评估，该反射记录自同侧股二头肌。通过重复施加恒定刺激强度，即三倍阈值（3T）来监测药理反应的时间演变。此外，通过将刺激强度从0变化到7T来构建募集曲线。RB101（7.5、15和30mg kg(-1)，静脉注射）引起反射的剂量依赖性、纳洛酮可逆性抑制，最高剂量时持续约60分钟。计算得出的ED(50)为16.9mg kg(-1)。对募集曲线的分析显示：（1）阈值显著升高；（2）曲线上升部分反射显著抑制；（3）对最强刺激（对应于曲线平台）引发的反应没有主要抑制作用。脑啡肽降解酶抑制剂使伤害性阈值升高，这证实了先前行为测试获得的数据。此外，本研究揭示了这些化合物在广泛的刺激强度范围内均有效，尽管不包括最高强度。
