Abstract
Biological actions of novel σ 1- and σ 2-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, α 2-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 σ 1- or σ 2-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.
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