Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain

Following nerve injury, primary sensory neurons (dorsal root ganglion [DRG] neurons, trigeminal neurons) exhibit a variety of electrophysiological abn ormalities, including increased baseline sensitivity and/or hyperexcitabili ty, which can lead to abnormal burst activity that underlies pain, but the molecular basis for these changes has not been fully understood. Over the p ast several years, it has become clear that nearly a dozen distinct sodium channels are encoded by different genes and that at least six of these (inc luding at least three distinct DRG- and trigeminal neuron-specific sodium c hannels) are expressed in primary sensory neurons. The deployment of differ ent types of sodium channels in different types of DRG neurons endows them with different physiological properties. Dramatic changes in sodium channel expression, including downregulation of the SNS/PN3 and NaN sodium channel genes and upregulation of previously silent type III sodium channel gene, occur in DRG neurons following axonal transection, These changes in sodium channel gene expression are accompanied by a reduction in tetrodotoxin (TTX )-resistant sodium currents and by the emergence of a TTX-sensitive sodium current which recovers from inactivation (reprimes) four times more rapidly than the channels in normal DRG neurons. These changes in sodium channel e xpression poise DRG neurons to fire spontaneously or at inappropriately hig h frequencies. Changes in sodium channel gene expression also occur in expe rimental models of inflammatory pain. These observations indicate that abno rmal sodium channel expression can contribute to the molecular pathophysiol ogy of pain. They further suggest that selective blockade of particular sub types of sodium channels may provide new, pharmacological approaches to tre atment of disease involving hyperexcitability of primary sensory neurons. ( C) 1999 John Wiley & Sons, Inc.