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.
Alzheimer
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Department of Physiology, University of Munich, Federal Republic of Germany.
ten Bruggencate
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D004399:Dynorphins / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa
D000700:Analgesics; D044482:Benzeneacetamides; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; C045444:U 69593