Sodium channels and pain

Although it is well established that hyperexcitability and/or increased bas eline sensitivity of primary sensory neurons can lead to abnormal burst act ivity associated with pain, the underlying molecular mechanisms are not ful ly understood. Early studies demonstrated that, after injury to their axons , neurons can display changes in excitability, suggesting increased sodium channel expression, and, in fact abnormal sodium channel accumulation has b een observed at the tips of injured axons. We have used an ensemble of mole cular, electrophysiological, and pharmacological techniques to ask: what ty pes of sodium channels underlie hyperexcitability of primary sensory neuron s after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs wi thin small dorsal root ganglion (DRG) neurons, which include nociceptive ce lls. Moreover, several DRG neuron-specific sodium channels now have been cl oned and sequenced. After injury to the axons of DRG neurons, there is a dr amatic change in sodium channel expression in these cells, with down-regula tion of some sodium channel genes and up-regulation of another, previously silent sodium channel gene. This plasticity in sodium channel gene expressi on is accompanied by electrophysiological changes that poise these cells to fire spontaneously or at inappropriate high frequencies. Changes in sodium channel gene expression also-are observed in experimental models of inflam matory pain. Thus, sodium channel expression in DRG neurons is dynamic, cha nging significantly after injury. Sodium channels within primary sensory ne urons may play an important role in the pathophysiology of pain.