Chiba Shunsuke, Nishiyama Tomoki, Yamada Yoshitsugu
Department of Anesthesiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.
Anesth Analg. 2009 Mar;108(3):1008-14. doi: 10.1213/ane.0b013e318193678f.
An isoindoline derivative, JM-1232(-) was developed as a sedative and analgesic drug. We performed the present study to investigate its antinociceptive effects on three different nociceptions in mice.
Mail ddY mice were administered intraperitoneal (i.p.) JM-1232(-) 1,3 or 10 mg/kg (n = 8 for each dose in each test). Saline was used as a control. The hotplate or tail pressure test was performed for 120 min after i.p. drug injection. Acetic acid 0.6% solution in 10 mL/kg was i.p. administered 15 min after i.p. drug injection in the acetic acid test. The number of abdominal constriction episodes was counted for 10 min, starting 5 min after i.p. administration of the acid. When the analgesic effect was observed, naloxone or flumazenil was subcutaneously administered before administration of the maximum effective dose of JM-1232(-). Using the wheel running test, the number of wheel revolutions was recorded every 5 min for 120 min.
In the hotplate, tail pressure and acetic acid tests, i.p. JM-1232(-) produced significant antinociceptive effects with a 50% effective dose of 2.96 mg/kg (CI: 2.65-3.30 mg/kg), 3.06 mg/kg (CI: 2.69-3.47 mg/kg) and 2.27 mg/kg (CI: 1.46-3.53 mg/kg), respectively. In all tests, JM-1232(-)-induced antinociception was antagonized by flumazenil (5 mg/kg) but not by naloxone (10 mg/kg). In the running wheel test, there was no dose-dependent effect of JM-1232(-) on locomotor activity.
Systemically administered JM-1232(-) had antinociceptive effects on acute thermal, mechanical-induced pain, and visceral pain in mice. These effects might be mediated by benzodiazepine-gamma-aminobutyric acid type A receptors but not by opioid receptors.
异吲哚啉衍生物JM-1232(-)被开发用作镇静和镇痛药。我们开展本研究以探究其对小鼠三种不同痛觉的镇痛作用。
雄性ddY小鼠腹腔注射1、3或10mg/kg的JM-1232(-)(每项试验中每个剂量n = 8)。生理盐水用作对照。腹腔注射药物后120分钟进行热板或尾压试验。在醋酸试验中，腹腔注射药物15分钟后腹腔注射10mL/kg的0.6%醋酸溶液。从腹腔注射醋酸5分钟后开始，计数10分钟内腹部收缩发作次数。当观察到镇痛效果时，在给予最大有效剂量的JM-1232(-)之前皮下注射纳洛酮或氟马西尼。使用跑步轮试验，每5分钟记录一次跑步轮转动次数，共记录120分钟。
在热板、尾压和醋酸试验中，腹腔注射JM-1232(-)产生显著的镇痛作用，其半数有效剂量分别为2.96mg/kg(CI：2.65 - 3.30mg/kg)、3.06mg/kg(CI：2.69 - 3.47mg/kg)和2.27mg/kg(CI：1.46 - 3.53mg/kg)。在所有试验中，JM-1232(-)诱导的镇痛作用被氟马西尼(5mg/kg)拮抗，但不被纳洛酮(10mg/kg)拮抗。在跑步轮试验中，JM-1232(-)对运动活动没有剂量依赖性影响。
全身给药的JM-1232(-)对小鼠急性热痛、机械性诱导疼痛和内脏疼痛具有镇痛作用。这些作用可能由苯二氮䓬 - γ-氨基丁酸A型受体介导，而非阿片受体。
