σ-Binding site ligands inhibit K⁺ currents in rat locus coeruleus neurons in vitro

Biological actions of novel σ₁- and σ₂-selective binding site ligands (trishomocubanes: 4-azahexacyclo [5.4.1.0.^2,6.0^3,10.0^5,9.0^8,11]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. σ-Ligands produced large inward currents in the presence of μ-opioid, α₂-adrenoceptor and ORL1 receptor agonists. These reversed polarity near the K⁺ equilibrium potential, suggesting that σ-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 σ₁- or σ₂-binding sites and potency to inhibit K⁺-currents, suggesting that these effects on K⁺-channels are not directly related to occupancy of σ binding sites. Copyright (C) 1998 Elsevier Science B.V.