Nonopioid actions of the kappa-opioid receptor agonists, U 50488H and U 69593 on electrophysiologic properties of hippocampal CA3 neurons in vitro.

The actions of the nonpeptide kappa-opioid receptor agonists, U 50488H (1-100 microM) and U 69593 (50-200 microM), on guinea pig hippocampal CA3 neurons were investigated in vitro by means of intra- and extracellular recording techniques. The compounds reduced the efficacy of synaptic transmission at the mossy fiber-CA3 synapse, and, simultaneously, enhanced the neuronal direct excitability. Intracellular recordings from CA3 neurons suggested two components underlying the drugs' excitatory actions: 1) Due to an apparent decrease in membrane leak conductance, the compounds enhanced the neuronal input resistance in a dose-dependent fashion. 2) The fast after-hyperpolarization following spontaneous or evoked action potentials was found to be substantially impaired in the presence of the drugs. In addition, extra- and intracellular recordings provided evidence that, by reducing the fast sodium conductance, both compounds exerted a local anesthetic action. The effects of U 50488H were antagonized neither by naloxone (2-50 microM) nor by the kappa-opioid receptor antagonist, nor-binaltorphimine (10-20 microM), indicating that the drug-induced effects represent unspecific actions not linked to activation of opioid receptors.