sigma-binding site ligands inhibit K+ currents in rat locus coeruleus neurons in vitro

Biological actions of novel sigma(1)- and sigma(2)-selective binding site l igands (trishomocubanes: 4-azahexacyclo [5.4.1.0.(2,6).0(3,10).0(5,9) 0(8,1 1)]dodecanes), and the reference Ligands, 1,3-di(2-tolyl)-guanidine (DTG), haloperidol, (+)-pentazocine and dextromethorphan, were studied in rat locu s coeruleus neurons using intracellular and whole cell patch clamp recordin gs. High concentrations of trishomocubanes produced small inward currents a nd 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, alpha( 2)-adrenoceptor and ORL1 receptor agonists. These reversed polarity near th e K+ equilibrium potential, suggesting that sigma-ligands act as ligand act ivated K+-channel blockers or interfere with the coupling between these rec eptors and K+-channels. However, no correlation was found between binding a ffinities at sigma(1)- or sigma(2)-binding sites and potency to inhibit K+- currents, suggesting that these effects an K+-channels are not directly rel ated to occupancy of a binding sites. (C) 1998 Elsevier Science B.V. All ri ghts reserved.