Biological actions of novel sigma1- and sigma2-selective binding site ligands (trishomocubanes: 4-azahexacyclo [5.4.1.0.(2,6).0(3,10).0(5,).0(8,11)]dodecanes), and the reference ligands, 1,3-di(2-tolyl)-guanidine (DTG), haloperidol, (+)-pentazocine and dextromethorphan, were studied in rat locus coeruleus neurons using intracellular and whole-cell patch clamp recordings. High concentrations of trishomocubanes produced small inward currents and affected some parameters of action potential waveforms suggesting modest potency to inhibit ionic conductances underlying action potentials. Sigma-ligands produced large inward currents in the presence of mu-opioid, alpha2-adrenoceptor and ORL1 receptor agonists. These reversed polarity near the K+ equilibrium potential, suggesting that sigma-ligands act as ligand activated K+-channel blockers or interfere with the coupling between these receptors and K+-channels. However, no correlation was found between binding affinities at sigma1- or sigma2-binding sites and potency to inhibit K+-currents, suggesting that these effects on K+-channels are not directly related to occupancy of sigma binding sites.