Sodium channels and pain

Voltage-gated sodium (Na+) channels play a key role in membrane excitation in neurons. These channels have a critical role in the development and maintenance of several pain syndromes, including inflammatory pain, neuropathic pain, and central pain associated with spinal cord injury.1–4 The increasing understanding of the molecular organization, function, and regulation of voltage-gated Na+ channels,5,6 their plasticity of expression following injury,4,7 and the clinical consequences of mutations8–12 provide insight into the important role of these channels in the pathophysiology of pain and rationale for development of channel subtype-specific drug therapy. Influx of Na+ through voltage-gated Na+ channels causes membrane depolarization, which is responsible for generation and conduction of the action potential in the axon and activation of presynaptic Ca2+ channels for exocytosis. Voltage-gated Na+ channels also modulate the resting membrane potential and subthreshold oscillations of the membrane potential, which determine the excitability of the neuron and its axon. The typical voltage-gated Na+ channel opens (activates) on membrane depolarization and then closes (inactivates) either rapidly on repolarization or more slowly on sustained depolarization. Fast inactivation is the primary mechanism of repolarization at the nodes of Ranvier, whereas slow inactivation regulates excitability and modulates burst discharges of neurons and axons. Toxins, local anesthetics, or mutations affecting single amino acid residue of the channel molecule affect the inactivation of voltage-gated Na+ channels.6 The voltage-gated Na+ channels are composed of an α-subunit consisting of four homologous domains (DI-DIV) and an auxiliary β-subunit5,6 (figure). Specific amino acid sequences of the α-subunit form the voltage sensor, the wall of the ion channel pore, the inactivation gate, the sites of binding for local anesthetics and toxins, and modulatory phosphorylation sites for several kinases The β-subunits modulate channel gating, inactivation, and cellular localization, …