Abstract
Unmyelinated C-fibers are a major type of sensory neurons conveying pain information. Action potential conduction is regulated by the bifurcation (T-junction) of sensory neuron axons within the dorsal root ganglia (DRG). Understanding how C-fiber signaling is influenced by the morphology of the T-junction and the local expression of ion channels is important for understanding pain signaling. In this study we used biophysical computer modeling to investigate the influence of axon morphology within the DRG and various membrane conductances on the reliability of spike propagation. As expected, calculated input impedance and the amplitude of propagating action potentials were both lowest at the T-junction. Propagation reliability for single spikes was highly sensitive to the diameter of the stem axon and the density of voltage-gated Na+ channels. A model containing only fast voltage-gated Na+ and delayed-rectifier K+ channels conducted trains of spikes up to frequencies of 110 Hz. The addition of slowly activating KCNQ channels (i.e., KV7 or M-channels) to the model reduced the following frequency to 30 Hz. Hyperpolarization produced by addition of a much slower conductance, such as a Ca2+-dependent K+ current, was needed to reduce the following frequency to 6 Hz. Attenuation of driving force due to ion accumulation or hyperpolarization produced by a Na+-K+ pump had no effect on following frequency but could influence the reliability of spike propagation mutually with the voltage shift generated by a Ca2+-dependent K+ current. These simulations suggest how specific ion channels within the DRG may contribute toward therapeutic treatments for chronic pain.
Highlights
SENSORY INFORMATION from the periphery, including pain, must pass through the dorsal root ganglion (DRG) before reaching the spinal cord
The diameter of the unmyelinated central axon is 50% smaller than the diameter of the peripheral axon (Ha 1970; Hoheisel and Mense 1986; Suh et al 1984; Zhang et al 1998). This is consistent with measurements of conduction velocity, which is generally faster in the peripheral axon compared with the central branch for both myelinated and unmyelinated sensory neurons (Czeh et al 1977; Obreja et al 2010; Raymond et al 1990; Suh et al 1984; Tigerholm et al 2014; Waddell et al 1989)
The major findings of this study are that 1) the T-junction will reduce the safety factor for spike propagation in an unmyelinated sensory neuron model based on peripheral and central axon morphology if the stem axon provides a sufficient conductance load, 2) the geometrical properties of the T-junction alone cannot account for low-pass filtering below 100 Hz, and 3) KCNQ channels can reduce following frequency down to ϳ30 Hz, whereas 4) a slower process, such as an SK Ca2ϩ-dependent Kϩ conductance, is needed to limit firing at lower frequencies
Summary
SENSORY INFORMATION from the periphery, including pain, must pass through the dorsal root ganglion (DRG) before reaching the spinal cord. Unmyelinated C-fibers are a major type of DRG sensory neuron conveying pain information, in addition to mechanical, chemical, and thermal stimuli (Dubin and Patapoutian 2010) They usually fire at rates Ͻ20 Hz (Chen and Levine 2003; Leem et al 1993; Long 1977; Yeomans et al 1996; Yeomans and Proudfit 1996) but may approach 100 Hz (Chen and Levine 2003; Kress et al 1992; Leem et al 1993; Yeomans et al 1996; Yeomans and Proudfit 1996), and high-frequency firing is www.jn.org believed to be important in the development of chronic pain (Fang et al 2002). We found that 1) the impedance mismatch from the T-junction alone does not account for adequate filtration of orthodromic signals and 2) slowly activating voltage-dependent Kϩ potassium currents (M-channels) may contribute in part to low-pass filtering, but 3) a slower, hyperpolarizing conductance [such as a small-conductance (SK)-like Ca2ϩ-dependent Kϩ channel] is required to reduce the following frequency to physiological levels
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