MD-354 selectively antagonizes the antinociceptive effects of (−)nicotine in the mouse tail-flick assay

Abstract

(-)Nicotine produces antinociceptive effects in rodents. meta-Chlorophenylguanidine (MD-354), an analgesia-enhancing agent, binds at 5-HT(3) and alpha(2)-adrenoceptors and potentiates the antinociceptive effects of an "inactive" dose of clonidine. The present study examined the actions of MD-354 on (-)nicotine-induced antinociception. Mouse tail-flick and other assays were employed. In the tail-flick assay, (-)nicotine (ED(50) = 1.66 mg/kg) but not MD-354 produced dose-related antinociceptive effects. Administered in combination with (-)nicotine (2.5 mg/kg), MD-354 (AD(50) = 3.4 mg/kg) did not potentiate, but effectively antagonized the antinociceptive actions of (-)nicotine. In a mouse hot-plate assay, MD-354 failed to modify (-)nicotine responses. In combination with a locomotor activity-suppressing dose of (-)nicotine, MD-354 (up to 17 mg/kg) failed to antagonize (-)nicotine-induced hypolocomotion. In a rat drug discrimination paradigm using (-)nicotine as training drug, MD-354 produced saline-appropriate responding; in combination with the training dose of (-)nicotine, MD-354 failed to antagonize the nicotine cue. MD-354 selectively antagonizes the antinociceptive actions of (-)nicotine in the tail-flick, but not in the hot-plate assay, or either the motor effects, or discriminative stimulus effects of (-)nicotine. The most parsimonious explanation is that MD-354 might act as a negative allosteric modulator of alpha 7 nACh receptors, and radioligand binding and functional data are provided to support this conclusion.