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ANALGESIA

The Antinociceptive Effects and Pharmacological Properties of JM-1232(-): A Novel Isoindoline Derivative

From the Department of Anesthesiology, The University of Tokyo, Tokyo, Japan.

Address correspondence and reprint requests to Shunsuke Chiba, MD, Department of Anesthesiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan. Address e-mail to chiba{at}bb.e-mansion.com.

Abstract

BACKGROUND: 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.

METHODS: Mail ddY mice were administered intraperitoneal (IP) 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 IP drug injection. Acetic acid 0.6% solution in 10 mL/kg was IP administered 15 min after IP drug injection in the acetic acid test. The number of abdominal constriction episodes was counted for 10 min, starting 5 min after IP 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.

RESULTS: In the hotplate, tail pressure and acetic acid tests, IP 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.

CONCLUSION: 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- -aminobutyric acid type A receptors but not by opioid receptors.