ANTINOCICEPTIVE AND TOXIC EFFECTS OF (+)-EPIBATIDINE OXALATE ATTRIBUTABLE TO NICOTINIC AGONIST ACTIVITY

1 Epibatidine is an analgesic substance, isolated from the skin of the poisonous frog Epipedobates tricolor, for which the mechanism of action was previously unknown. 2 The IC50 of synthetic (+)-epibatidine oxalate (the naturally occurring isomer) for [H-3]-nicotine binding to rat whole-brain membranes was 0.1 nM. The (-)-isomer also exhibited high affinity (IC50 = 0.2 nM). 3 (+)- and (-)-Epibatidine exhibited much lower affinity for displacement of the muscarinic ligand [H-3]-N-methylscopolamine binding to rat cortical membranes (K-app = 6.9 mu M and 16.0 mu M respectively). The (+)-enantiomer of epibatidine had an antagonist/agonist (NMS/oxo-M) binding ratio of 4.2 This is consistent with a muscarinic antagonist profile. 4 (+)-Epibatidine oxalate (10 mu M) did not cause significant (>30%) displacement of radioligand binding to opioid, excitatory amino acid, benzodiazepine, 5-HT, dopamine, adrenaline or peptide receptors. 5 (+)- and (-)-Epibatidine (5-20 mu g kg(-1) s.c.) doubled response latency in the mouse hot-plate test. Antinociception and behavioural depression induced by (+)-epibatidine (5 mu g kg(-1)) was fully blocked by the nicotinic antagonists mecamylamine (2 mg kg(-1) s.c.) or dihydro-beta-erythroidine (2 mg kg(-1) s.c.). The muscarinic antagonist scopolamine (0.4 and 10 mg kg(-1) s.c.) caused partial reversal of antinociception induced by (+)-epibatidine in mice, but not in rats. 6 These findings demonstrate that(+)-epibatidine oxalate salt is a highly selective and potent nicotinic analgesic agent.