Voltage-gated sodium channels and the molecular pathogenesis of pain: A review

Pain pathways begin with spinal sensory (dorsal root ganglion, DRG) neurons that produce nociceptive signals and convey them centrally. Following inju ry to the nervous system, DRG neurons can become hyperexcitable, generating spontaneous action potentials or abnormal high-frequency activity that con tributes to chronic pain. Because the generation of action potentials in DR G neurons depends on voltage-gated sodium channels, an understanding of the expression and function of these channels in DRG neurons is important for an understanding of pain. Molecular studies have indicated that at least ei ght distinct voltage-gated sodium channels, sharing a common overall motif but encoded by different genes that endow them with different amino acid se quences, are present within the nervous system. The DRG neurons express six different sodium channels, including several sensory-neuron-specific sodiu m channels that are not present at significant levels within other parts of the nervous system. Following injury to their axone within peripheral nerv e, DRG neurons down-regulate some sodium channel genes, and up-regulate oth ers. As a result, a different repertoire of sodium channels is inserted int o the DRG neuron cell membrane following injury, which is a molecular chang e that is accompanied by changes in physiological properties that contribut e to hyperexcitability in these cells. Sodium channel expression is also al tered in experimental models of inflammatory pain. The multiplicity of sodi um channels, and the dynamic nature of their expression, makes them importa nt targets for pharmacologic manipulation in the search for new therapies f or pain.