The unusual nature of epibatidine responses at the alpha 4 beta 2 nicotinic acetylcholine receptor

The identification of an equatorial frog toxin, epibatidine, as a potent no n-morphinic analgesic, selective for neuronal nicotinic acetylcholine recep tors, provoked a marked renewal in our understanding of pain and its mechan isms. In this work we have examined the effects of epibatidine at the major brain rat alpha4 beta2 nicotinic acetylcholine receptor expressed in a cel l line. Fast drug applications obtained with a modified liquid filament sys tem were used for the analyses of the currents evoked by acetylcholine, nic otine and epibatidine. Characterized by a slow onset and offset, epibatidin e responses were of smaller amplitude to those evoked by acetylcholine or n icotine. About a thousand times more sensitive to epibatidine than acetylch oline, the alpha4 beta2 receptor also displayed a more pronounced apparent desensitization to this compound. Finally, overnight exposure to 1 nM epiba tidine failed to produce the functional upregulation observed with nicotine . These data indicate that, at the rat alpha4 beta2 receptor, epibatidine a cts as a partial agonist causing a pronounced inhibition of agonist evoked currents at concentrations that do not activate the receptors. (C) 2000 Els evier Science Ltd. All rights reserved.