Activation of ''voltage-sensitive sodium channels'' (VSSC) is responsible for the rapid upstroke of the action potential. Ten molecularly distinct pore-forming subunits (a-subunits) of VSSC have been identified and are generally referred to as Nav 1.1 to Nav 1.9 (59). The most striking difference between these channels is their sensitivity to the neurotoxin, tetrodotoxin (TTX). While nanomolar concentrations of TTX completely block sodium currents in neurons
within the central nervous system, a fraction of the voltage-sensitive sodium current in primary sensory neurons persists even in micromolar TTX concentrations. As shown in Figure 5, this TTX-resistant current activates and inactivates more slowly than the TTX-sensitive current. Because of the different kinetic properties, a significant contribution of TTX-resistant current prolongs the action potential. Interestingly, this TTX-resistant current is primarily found in small diameter, unmyelinated neurons (C-fibers), which are important in nociception (60,61). No selective blockers of TTX-resistant sodium channels are currently available to directly test their importance in pain sensation. Therefore, two complementary approaches employed genetic manipulations, decreasing or eliminating Nav1.8 expression using antisense oligodeoxynucleotides or knockout mice, which led to a blunted response to noxious mechanical stimulation or inflammatory pain (62,63). Conversely, experimental models of visceral inflammation and pain are associated with an increase in TTX-resistant sodium currents (Fig. 5). While these results all point at a central role of TTX-resistant sodium currents in nociception, functional changes are not restricted to this sodium channel. In addition, the properties of TTX-sensitive sodium channels are altered with a shift in the voltage-dependence of activation to less depolarized potentials and a faster recovery from inactivation. The increase in channel expression, changes in voltage-dependence, and recovery kinetics together will lower the threshold for action potential generation and contribute to higher spike frequencies (64-66).
Two primary mechanisms have been described that alter sodium currents in primary sensory neurons: covalent modulation through phosphorylation and changes in channel expression. Phosphorylation of the pore-forming channel subunit shifts the voltage dependence of activation to more negative potentials (67). Several inflammatory mediators activate protein kinases, which then in turn phosphorylate sodium channels (68-70). As discussed above, 5-HT may play a unique role as a chemical mediator within the gastrointestinal tract, considering its functions as a physiological signal that is released from enteroendocrine cells upon mechanical or chemical stimulation. Interestingly, activation of metabotropic 5-HT receptors enhances TTX-resistant sodium currents in primary afferent neurons (71,72). While it remains unclear whether 5-HT similarly affects all visceral afferent neurons (73), this mechanism may contribute to peripheral sensitization.
The expression of sodium channels appears to be regulated by target-derived factors produced by cells within the vicinity of sensory endings. Axotomy, which deprives the neuron of these signals, decreases sodium channel expression and reduces excitability (74-76). Conversely, signals released during inflammation increase sodium channel expression, thereby contributing to peripheral sensitization (77). As already discussed above, NGF is one of these target-derived signals and is involved in the regulation of sodium channel expression. Administration of NGF to the cut end of the axon prevents the decrease in Nav1.8
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