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DW Bonhaus, KR Bley, CA Broka, DJ Fontana, E Leung, R Lewis, A Shieh and EH Wong
Department of Neurosciences, Syntex Discovery Research, Palo Alto, California.
Epibatidine has been reported to be a potent, nonopioid analgesic. In this study we further characterized its receptor interactions and its analgesic properties. Radioligand binding assays demonstrated that epibatidine has high affinity for nicotinic receptors (Ki = 0.12 nM) but low affinity for opioid and other receptors (Ki > 3.0 microM). In vitro functional assays demonstrated that the compound is a potent agonist at both neuronal and neuromuscular nicotinic receptors. Epibatidine depolarized rat isolated vagus nerve with an EC50 of 33.1 nM and contracted guinea pig ileum with an EC50 of 6.1 nM. Epibatidine contracted frog rectus abdominis muscle with an EC50 of 18.2 nM. In vivo, epibatidine demonstrated short-lived analgesic actions. Epibatidine (10 and 30 micrograms/kg), at 5 but not 20 min after dosing, increased the threshold for vocalization evoked by foot shock. Epibatidine, at 5 and 20 but not 60 min after dosing, also increased the latency to a nociceptive response in a hot-plate assay. Both (+)- and (-)-enantiomers of epibatidine were active in these assays. The action of epibatidine in the hot-plate test was reversed by the nicotinic receptor antagonist mecamylamine but not by the opioid receptor antagonist naloxone. In contrast to morphine, epibatidine failed to increase locomotor activity. These findings demonstrate that epibatidine is a potent agonist at both neuronal and neuromuscular nicotinic receptors. These findings also demonstrate a short-lived, naloxone-insensitive, analgesic action for both the (+)- and (-)- enantiomers of epibatidine.(ABSTRACT TRUNCATED AT 250 WORDS)
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