Sigma receptor activation inhibits voltage-gated sodium channels in rat intracardiac ganglion neurons.

Sigma (σ) receptors have been shown to regulate multiple ion channel types in intracardiac ganglion neurons, including voltage-gated calcium and potassium channels. However, the inhibition of these channels alone cannot fully account for σ receptor-induced changes in neuronal excitability previously reported. Whole-cell patch clamp experiments were conducted under current-clamp mode in isolated intracardiac neurons from neonatal rats to assess the effects of σ receptor activation on the active membrane properties of these cells. Bath application of the pan-selective σ receptor agonist, 1,3-Di-o-tolylguanidine (DTG), and the σ-1-selective agonist, (+)-pentazocine, significantly increased the action potential latency and decreased action potential overshoot in response to depolarizing current ramps, which suggests inhibition of voltage-gated sodium channels. Whole-cell voltage clamp experiments showed that these σ agonists reversibly decrease depolarization-activated Na(+) currents in these cells at all potentials tested. The peak currents generated by membrane depolarizations were decreased in a dose dependent manner with IC(50) values for DTG and (+)-pentazocine of 32 μM and 49 μM, respectively. The σ-1 receptor-selective antagonist, BD 1063 (100 nM), inhibited DTG (30 μM) block of Na(+) currents by ∼ 50%, suggesting that the effects are mediated by activation of σ-1 receptors. DTG also shifted the steady-state inactivation curve of Na(+) channels to more negative potentials, with the membrane potential of half-activation shifting from -49 mV to -63 mV in the absence and presence of 30 μM DTG, respectively. Taken together, these results suggest that σ-1 receptor activation decreases intracardiac ganglion neuron excitability by modulating voltage-gated Na(+) channels.