Sodium channels and pain

Although it is well established that hyperexcitability andyor increased baseline sensitivity of primary sensory neurons can lead to abnormal burst activity associated with pain, the underlying molecular mechanisms are not fully 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 been observed at the tips of injured axons. We have used an ensemble of molecular, electrophysiological, and pharmacological techniques to ask: what types of sodium channels underlie hyperexcitability of primary sensory neurons after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Moreover, several DRG neuron-specific sodium channels now have been cloned and sequenced. After injury to the axons of DRG neurons, there is a dramatic change in sodium channel expression in these cells, with down-regulation of some sodium channel genes and up-regulation of another, previously silent sodium channel gene. This plasticity in sodium channel gene expression 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 inf lammatory pain. Thus, sodium channel expression in DRG neurons is dynamic, changing significantly after injury. Sodium channels within primary sensory neurons may play an important role in the pathophysiology of pain. Pain pathways begin with primary sensory neurons [dorsal root ganglion (DRG) neurons; trigeminal neurons]. It is now clear that, in some pain syndromes, hyperexcitability andyor increased baseline sensitivity of these cells leads to abnormal bursting that can produce chronic pain (1–3). The pivotal position of primary sensory neurons as distal sites of impulse generation along the nociceptive pathway, and the experimental and clinical accessibility of these neurons, has resulted in intense interest in mechanisms underlying action potential generation and transmission in them in disease states characterized by pain. Voltage-gated sodium channels, which produce the inward membrane current necessary for regenerative action potential production within the mammalian nervous system, are, of course, expressed in primary sensory neurons and have emerged as important targets in the study of the molecular pathophysiology of pain and in the search for new pain therapies. In this paper we focus on the potential role of sodium channels in the molecular pathophysiology of pain. We will emphasize, in particular, three motifs: first, that DRG neurons express a complex repertoire of multiple distinct sodium channels, encoded by different genes; second, that some of these sodium channels are sensory neuron specific; and third, that sodium channel expression in DRG neurons is highly dynamic, changing substantially not only during development, but also in various disease states, including some that are accompanied by pain. Hyperexcitability in DRG Cells After Injury Early studies (4, 5) demonstrated that, after injury to their axons, motor neurons display changes in excitability, suggesting increased sodium channel expression over the cell body and the dendrites, and similar changes were subsequently observed in sensory neurons (6, 7). Abnormal sodium channel accumulation at the tips of injured axons also has been observed (8–10), and both electrophysiological and computer simulation studies have suggested that abnormal increases in sodium conductance can lead to inappropriate, repetitive firing (11– 13). Indeed, there is substantial evidence indicating that the abnormal excitability of DRG neurons, after axonal injury, is associated with an increased density of sodium channels (13, 14). These observations, together with experimental and clinical observations on partial efficacy of sodium channelblocking agents in neuropathic pain (15–18), established a link between sodium channel activity and sensory neuron hyperexcitability producing pain. However, these studies did not examine the crucial question: what type(s) of sodium channels produce inappropriate sensory neuron discharge associated with pain? Multiple Sodium Channels in Primary Sensory Neurons Over the past decade, it has become clear that nearly a dozen, molecularly distinct voltage-gated sodium channels are encoded within mammals by different genes. DRG neurons, which had been known to display multiple, distinct sodium currents (19–22), express at least six sodium channel transcripts (23), as illustrated by the in situ hybridizations and reverse transcription–PCR shown in Figs. 1 and 2. These include high levels of expression of the a-I and Na6 channels, also expressed at high levels by other neuronal cell types within the central nervous system, which are known to support tetrodotoxin (TTX)-sensitive sodium currents. In addition, DRG neurons are unique in expressing four additional sodium channel transcripts that are not expressed at significant levels in other neuronal cell types: (i) PN1yhNE, which is expressed preferentially in DRG neurons (24), produces a fast, transient TTX-sensitive sodium current in response to sudden depolarPNAS is available online at www.pnas.org. Abbreviations: DRG, dorsal root ganglia; TTX; tetrodotoxin; NGF, nerve growth factor. *To whom reprint requests should be addressed at: Department of Neurology, LCI 707, Yale Medical School, 333 Cedar Street, New Haven, CT 06510. e-mail: [email protected].