Tomizawa_2001_Toxicol.Appl.Pharmacol_177_77

Several nicotinic agonists with the 6-chloro-3-pyridinyl moiety are potent insecticides (e.g., the neonicotinoids imidacloprid and thiacloprid) while others are candidate nonopioid and nonantiinflammatory analgesics (i.e., epibatidine and several heterocyclic analogs). This study examines the hypothesis for the first time that the neonicotinoid insecticides and their imine metabolites and analogs display analgesic (antinociceptive) activity or adverse toxic effects associated with their action on binding to the alpha 4 beta 2 nicotinic acetylcholine receptor (AChR) subtype. Seven 6-chloro-3-pyridinyl compounds were studied, i.e., imidacloprid and thiacloprid, the corresponding imines and an olefin derivative, a nitromethylene analog, and (+/-)-epibatidine. Like (-)-nicotine and carbachol, they all act as full agonists in the (86)rubidium ion efflux experiment with intact mouse fibroblast M10 cells stably expressing the alpha 4 beta 2 nicotinic AChR. Their agonist action is correlated with binding affinity to the alpha 4 beta 2 receptor from M10 cells. Imidacloprid, thiacloprid, and their imine analogs are not antinociceptive agents in mice by abdominal constriction and hot plate analgesic tests. Their agonist actions at the alpha 4 beta 2 receptor correlate instead with their toxicity. Surprisingly, the nitromethylene analog, a weak agonist, is as potent as (-)-nicotine in inducing antinociception, and the effect persists longer than that caused by (-)-nicotine. However, mecamylamine (1 mg/kg) prevents antinociception induced by (-)-nicotine but not by the nitromethylene analog. Interestingly, this nitromethylene neonicotinoid insecticide gives 80-100% mortality within 15 min at 3 mg/kg with mecamylamine pretreatment at 2 mg/kg, doses at which each agent alone gives no lethality. Therefore, analgesic and toxic effects of the nitromethylene analog differ in their mechanism of action from (-)-nicotine and (+/-)-epibatidine.