Research ArticleNEUROSCIENCE

Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current

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Science Advances  11 Apr 2018:
Vol. 4, no. 4, eaaq1438
DOI: 10.1126/sciadv.aaq1438
  • Fig. 1 Model of neural membrane responses of a 10-μm axon (like the Aβ sensory fiber) versus a small 1-μm axon (like the pain-carrying C fiber) to a −500-μA stimulus delivered at 1-mm distance at x = 0 cm for varying durations.

    (A) Membrane potential along the neuron of the two fibers after 100 μs of stimulation. (B) Membrane potential of the two fibers after 1 s of stimulation. (C) Maximum membrane voltage of the two fibers as a function of stimulus duration.

  • Fig. 2 Model of the AP block and the effect of two types of channels on the block threshold.

    (A) Model results showing the propagation of AP in the large 10-μm Aβ fiber model sufficiently blocked at 0 cm on the left and insufficiently blocked on the right. (B) Small-diameter unmyelinated axon (1 μm) and large-diameter myelinated axon (10 μm) are populated programmatically with the models of Nav 1.7 or Nav 1.6 VGSCs, respectively. Bars on the left show the stimulation threshold for a 500-μs pulse necessary to depolarize the 10-μm Aβ fiber (gray) versus the 1-μm unmyelinated C fiber (red). The bars on the right show the respective amplitude of the iDC necessary to block the propagation of AP in the Aβ versus the C fibers.

  • Fig. 3 Cathodic iDC at the sciatic nerve induces inhibition of AP conduction in the peripheral nerve.

    (A) Experimental setup for recording CAPs at the dorsal root in response to a test pulse (5 mA, 0.5 ms) applied at the distal sciatic nerve in rats. Monopolar cathodic iDC (0.1 to 0.8 mA, 2 min per amplitude) was applied to the sciatic nerve at mid-thigh level. DRG, dorsal root ganglion. (B) Examples of dorsal root CAPs evoked by the test stimulation before and after iDC stimulation. CAPs reveal two distinct groups of waves corresponding to Aα/β fiber and Aδ fiber activation. The amplitude of each CAP was measured from the positive peak to the negative peak of the waveform. (C) The amplitudes of Aα/β and Aδ CAPs decreased progressively as amplitudes of iDC stimulation increased (0.1 to 0.8 mA, 2 min per amplitude) and gradually recovered at 1 to 5 min after iDC stimulation. *P < 0.05 versus pre-iDC baseline; #P < 0.05 versus the indicated group at post-iDC, two-way repeated-measures analysis of variance (ANOVA) with Tukey post hoc test. Data are mean + SEM (n = 7).

  • Fig. 4 Cathodic iDC at the sciatic nerve suppresses spinal LFP to peripheral test stimulation in an intensity-dependent manner.

    (A) Experimental setup for recording LFP from the superficial dorsal horn at the L4 spinal level to a test pulse (25 V, 0.5 ms) applied at the distal sciatic nerve in rats. Monopolar cathodic iDC stimulation was applied to the sciatic nerve at mid-thigh level. (B) Example traces show spinal LFP evoked by test stimulation before and after iDC stimulation. LFPs corresponding to A fiber and C fiber activation were distinguished on the basis of latency. The peak amplitude of A-LFP and area under the curve (AUC; shaded area) of C-LFP were measured off-line. (C) The amplitude of A-LFP and AUC of C-LFP decreased progressively as amplitudes of iDC increased (0.1 to 0.8 mA, 2 min per amplitude) and gradually recovered during the first 5 min after iDC cessation.*P < 0.05 versus pre-iDC baseline; #P < 0.05 versus the indicated group at post-iDC, two-way repeated-measures ANOVA with Tukey post hoc test. Data are mean + SEM (n = 8).

  • Fig. 5 Cathodic iDC at the sciatic nerve induces preferential inhibition of WDR neuronal responses to nociceptive afferent inputs.

    (A) Experimental setup for recording of WDR neurons from the dorsal horn to a test pulse (5 mA, 2 ms) applied to the hind paw of rats. Monopolar cathodic iDC stimulation (0.1 to 0.8 mA, 2 min per amplitude) was applied to the sciatic nerve at mid-thigh level. (B) Example of WDR neuron responses evoked by the test stimulation before and after iDC stimulation. WDR neuron responses can be divided into Aβ (0 to 25 ms), Aδ (25 to100 ms), and C (100 to 500 ms) components in rats based on the activation threshold and response latency. (C) The number of APs evoked in WDR neurons by test stimulation decreased as amplitudes of iDC increased (0.1 to 0.8 mA, 2 min per amplitude) and increased in the first 5 min after iDC stimulation ended. *P < 0.05 versus pre-iDC baseline; #P < 0.05 versus the indicated group at post-iDC; two-way repeated-measures ANOVA with Tukey post hoc test. Data are expressed as mean + SEM, n = 11.

  • Fig. 6 Markov state transition model of the VGSCs.

    I1 and I2 are the inactivated states, C1 and C2 are closed states, and O1 and O2 are open states. Adapted with permission from Balbi et al. (25).

Supplementary Materials

  • Supplementary Materials

    This PDF file includes:

    • fig. S1. Example of a real-time output of the MATLAB script provided in the Supplementary Materials.

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    Other Supplementary Material for this manuscript includes the following:

    • data file S1. iDCBlock.m MATLAB script that implements the model described in the publication. See the supplementary instructions for using this script.

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