ANTINOCICEPTIVE EFFECTS OF THE NOVEL NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR AGONIST, ABT-594, IN MICE

ABT-594 [5-((2R)-azetidinylmethoxy)-2-chloropyridine], a novel neurona l nicotinic acetylcholine receptor agonist, produced significant antin ociceptive effects in mice against both acute noxious thermal stimulat ion-the hot-plate and cold-plate tests-and persistent visceral irritat ion-the abdominal constriction (writhing) assay (maximally-effective d ose in each test 0.62 mu mol/kg, i.p.). This effect was not stereosele ctive since the S-enantiomer, A-98593 [5-((2S)-azetidinylmethoxy)-2-ch loropyridine], produced similar antinociceptive effects in this dose r ange. The effect in the hot-plate test peaked at 30 min after i.p. adm inistration and was still present 60 min, but not 120 min, after injec tion. ABT-594 was orally active, but 10-fold less potent by this route than after i.p. administration. The antinociceptive effect of ABT-594 was prevented, but not reversed, by the noncompetitive neuronal nicot inic acetylcholine receptor antagonist mecamylamine (5 mu mol/kg, i.p. ). In contrast, the antinociceptive effect of ABT-594 was not prevente d by hexamethonium (10 mu mol/kg, i.p.), a neuronal nicotinic acetylch oline receptor antagonist that does not readily enter the central nerv ous system, nor by naltrexone (0.8 mu mol/kg), an opioid receptor anta gonist. Thus, initiation of antinociception by ABT-594 involves activa tion of central nicotinic acetylcholine receptors, but does not requir e activation of naltrexone-sensitive opioid receptors. The antinocicep tive effects of morphine and ABT-594 in the mouse hot-plate test appea red to be additive, but ABT-594 did not potentiate the respiratory dep ression produced by morphine when the two compounds were coadministere d. ABT-594 reduced body temperature and spontaneous exploration in the antinociceptive dose range, but did not reliably impair motor coordin ation in the rotarod test. Thus, it is unlikely that the antinocicepti ve effects result simply from impaired motor function. The compound al so produced an anxiolytic-like effect in the elevated plus maze (at 0. 019 and 0.062 mu mol/kg, i.p.). Preliminary safety testing revealed an EDS, for overt seizure production of 1.9 mu mol/kg, i.p. and an LD,, of 19.1 mu mol/kg i.p. in mice, values 10 and 100 times the minimum ef fective antinociceptive dose of the compound. ABT-594 increased the du ration of ethanol-induced hypnotic effects, tended to increase pentoba rbital-induced hypnotic effects (P = 0.0502), and had no effect on pen tobarbital-induced lethality. These data indicate that ABT-594 is a ce ntrally acting neuronal nicotinic acetylcholine receptor agonist with potent antinociceptive and anxiolytic-like effects in mice. (C) 1998 E lsevier Science B.V.