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Antinociceptive and toxic effects of (+)‐epibatidine oxalate attributable to nicotinic agonist activity
Author(s) -
Rupniak N.M.J.,
Patel S.,
Marwood R.,
Webb J.,
Traynor J.R.,
Elliott J.,
Freedman S.B.,
Fletcher S.R.,
Hill R.G.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17164.x
Subject(s) - epibatidine , chemistry , flumazenil , mecamylamine , nicotinic agonist , pharmacology , antagonist , stereochemistry , receptor , nicotinic acetylcholine receptor , biology , biochemistry
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 IC 50 of synthetic (+)‐epibatidine oxalate (the naturally occurring isomer) for [ 3 H]‐nicotine binding to rat whole‐brain membranes was 0.1 n m . The (−)−isomer also exhibited high affinity (IC 50 = 0.2 n m ). 3 (+)‐ and (−)−Epibatidine exhibited much lower affinity for displacement of the muscarinic ligand [ 3 H]‐N‐methylscopolamine binding to rat cortical membranes ( K app − 6.9μ m and 16.0 μ 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 μ 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 μg kg −1 s.c.) doubled response latency in the mouse hot‐plate test. Antinociception and behavioural depression induced by (+)‐epibatidine (5 μg kg −1 ) was fully blocked by the nicotinic antagonists mecamylamine (2 mg kg −1 s.c.) or dihydro‐β‐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.