Modulation of voltage-dependent sodium channels by the δ-agonist SNC80 in acutely isolated rat hippocampal neurons

Following activation, voltage-gated Na+ currents (I-Na) inactivate on two different time scales: fast inactivation takes place on a time scale of milliseconds, while slow inactivation takes place on a time scale of seconds to minutes. Both fast and slow inactivation processes govern availability of Na+ channels. In this study, the effects of the delta-opioid receptor agonist SNC80 on slow and fast inactivation of IN,, in rat hippocampal granule cells were analyzed in detail. Following application of SNC80, a block of the peak Na+ current amplitude (EC50: 50.6 muM, Hill coefficient: 0.518) was observed. Intriguingly, SNC80 (50 muM) also caused a selective effect on slow but not fast inactivation processes, with a notable increase in the fraction of Na+ channels undergoing slow inactivation during prolonged depolarization. In addition, recovery from slow inactivation was considerably slowed. At the same time, fast recovery processes were unaffected. The effects of SNC80 were not mimicked by the peptide delta-receptor agonist DPDPE (10 muM), and were not inhibited by the opioid receptor antagonists naloxone (50-300 muM) or naltrindole (10 and 100 muM), indicating an opioid receptor independent modulation of Na+ channels. These data suggest that SNC80 not only affects delta-opioid receptors, but also voltage-gated Na+ channels. SNC80 is to our knowledge hitherto the only substance that selectively influences slow but not fast inactivation processes and could provide an important tool in unraveling the mechanism underlying these distinct biophysical processes. (C) 2004 Elsevier Ltd. All rights reserved.