We recently synthesized a bridged-nicotine (BN) analog and its enantiomers. They failed to compete for [3H]nicotine binding in rat brain homogenates, yet they produced nicotine-like effects by decreasing locomotor activity and producing antinociception in the tail-flick, hot-plate and PPQ tests in mice. Therefore, additional in vivo and in vitro studies were undertaken to determine whether these compounds are indeed acting independently of the nicotinic system. Although these analogs did not produce nicotine-like responding when evaluated in rat drug discrimination, the racemate augmented the cue when administered in conjunction with nicotine. Moreover, the antinociceptive measured in the different tests and hypothermic effects of (+)-BN, the more potent enantiomer, were not blocked by the nicotinic antagonists mecamylamine and dihydro-beta-erythroidine. Acute tolerance developed to (+)-BN-induced antinociception but not to hypothermia after subcutaneous administration. In addition, no cross-tolerance was observed between (+)-BN and nicotine in the different tests. The absence of generalization in the discrimination test suggests that the BN analogs do not possess nicotine-like activity. In addition, the failure of mecamylamine and dihydro-beta-erythroidine to antagonize the antinociceptive and hypothermic effects of (+)-BN, on one hand, and the inability of the bridge analogs to stimulate 86Rb+ efflux in brain synaptosomes, on the other hand, provide further evidence that BN analog agonist effects are not mediated by the alpha-4, beta-2 receptor subunit combination. It is unlikely that alpha-7 subunits mediate the agonists effects of BN analogs because their affinity to neuronal [125I]alpha-bungarotoxin binding sites is in the higher micromolar range. Other nicotinic receptor subtypes remain possible candidates because (+/-)-BN augments the generalization of nicotine in drug discrimination and produces some nicotine-like pharmacological effects. BN analogs could represent a novel class of nicotinic analgesics because naloxone and atropine failed to alter the antinociceptive effects of (+)-BN. Alternatively, their actions may be entirely independent of the nicotinic system.