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

Abstract

Following nerve injury, primary sensory neurons (dorsal root ganglion [DRG] neurons, trigeminal neurons) exhibit a variety of electrophysiological abnormalities, including increased baseline sensitivity and/or hyperexcitability, which can lead to abnormal burst activity that underlies pain, but the molecular basis for these changes has not been fully understood. Over the past 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 (including at least three distinct DRG‐ and trigeminal neuron–specific sodium channels) are expressed in primary sensory neurons. The deployment of different 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 expression poise DRG neurons to fire spontaneously or at inappropriately high frequencies. Changes in sodium channel gene expression also occur in experimental models of inflammatory pain. These observations indicate that abnormal sodium channel expression can contribute to the molecular pathophysiology of pain. They further suggest that selective blockade of particular subtypes of sodium channels may provide new, pharmacological approaches to treatment of disease involving hyperexcitability of primary sensory neurons. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22:1177–1187, 1999

Kv1.4 Subunit Expression is Decreased in Neurons of Painful Human Pulp

“…However, in addition to decreased K ϩ channels, injury to sensory nerves increases the expression of some Na ϩ channels (27)(28)(29) and also causes the emergence of tetrodotoxin-sensitive Na ϩ current (6), and therefore it is likely that reductions in Kv1.4 subunits and I A work in concert with increases in Na ϩ currents to increase the excitability of primary sensory axons innervating tooth pulp.…”

Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain

“…[4][5][6] Considerable data indicate that hyperexcitability and spontaneous action potential firing mediated by VGSCs in peripheral sensory neurons play a role in the pathophysiology of chronic pain. 7,8 Consistent with this hypothesis, non-selective blockade of sodium channels contributes to the analgesic activity of a number of clinically used agents, such as mexiletine, lamotrigine, and carbamazepine, all of which were developed for other indications. Unfortunately, the adverse events observed with these drugs limits their clinical utility for the treatment of chronic pain.…”

Enhanced SCN7A/Nax expression contributes to bone cancer pain by increasing excitability of neurons in dorsal root ganglion

“…This leak Na+ current appears sufficient to depolarize neurons to generate ectopic spiking which leads to central sensitization of chronic pain. The level of ectopic discharge is generally well correlated with the degree of pain behavior in neuropathic animals (Sheen and Chung, 1993;Waxman et al, 1999;Xie et al, 2011). A slight reduction of the leak Na+ current contributes to hyperpolarization of neurons and decreases excitability.…”