Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats

The present study directly compared the antinociceptive and toxic effects o f the neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmetho xy)-2-chloropyridine) with(-)-nicotine and (+)-epibatidine. Like (-)-nicoti ne (0.8 and 1.6 mg/kg s.c.) and(+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05 and 0.1 mg/kg s.c.) increased response latencies in the hot- plate test in rats, indicating that it has antinociceptive activity. In con trast to (-)-nicotine and (+)-epibatidine, ABT-594 did not cause rotarod im pairment at antinociceptive doses but did cause hypothermia and life-threat ening adverse effects including seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1 and 0.03 mg/kg i.v.) and (+)-epibatid ine (0.001 and 0.003 mg/kg i.v.). Both the antinociceptive and toxic effect s (convulsions and hypertension) were abolished by pretreatment with the br ain penetrant neuronal nAChR antagonist mecamylamine (1 mg/kg s.c.; i.v. fo r cardiovascular studies), demonstrating that these actions of ABT-594 were mediated via activation of neuronal nicotinic receptors. Continuous infusi on of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days followed by chall enge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like abstinence sy ndrome suggesting that ABT-594 has nicotine-like dependence liability. Thes e findings indicate that the acute safety profile of ABT-594 is not signifi cantly improved over other nicotinic analgesics. (C) 2000 International Ass ociation for the Study of Pain. Published by Elsevier Science B.V. All righ ts reserved.