CHARACTERIZATION OF THE ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND BEHAVIORAL ACTIONS OF EPIBATIDINE

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 epi batidine has high affinity for nicotinic receptors (K-i=0.12 nM) but l ow affinity for opioid and other receptors (K-i>3.0 mu M). In vitro fu nctional assays demonstrated that the compound is a potent agonist at both neuronal and neuromuscular nicotinic receptors. Epibatidine depol arized rat isolated vagus nerve with an EC(50) of 33.1 nM and contract ed guinea pig ileum with an EC(50) of 6.1 nM. Epibatidine contracted f rog rectus abdominis muscle with an EC(50) of 18.2 nM. In vivo, epibat idine demonstrated short-lived analgesic actions. Epibatidine (10 and 30 mu g/kg), at 5 but not 20 min after dosing, increased the threshold for vocalization evoked by foot shock. Epibatidine, at 5 and 20 but n ot 60 min after dosing, also increased the latency to a nociceptive re sponse in a hot-plate assay. Both (+)- and (-)-enantiomers of epibatid ine were active in these assays. The action of epibatidine in the hot- plate test was reversed by the nicotinic receptor antagonist mecamylam ine but not by the opioid receptor antagonist naloxone. In contrast to morphine, epibatidine failed to increase locomotor activity. These fi ndings demonstrate that epibatidine is a potent agonist at both neuron al and neuromuscular nicotinic receptors. These findings also demonstr ate a short-lived, naloxone-insensitive, analgesic action for both the (+)- and (-)-enantiomers of epibatidine. The low affinity of epibatid ine for opioid receptors, the failure of naloxone to reverse the analg esic response and the failure of epibatidine to produce opioid-like be haviors confirm that epibatidine has a nonopioid mechanism of action.