Sodium channels in pain disorders: pathophysiology and prospects for treatment

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Pain is deemed chronic if it lasts more than 12 weeks and can sometimes last a lifetime. Although some clinical pain syndromes are traced back to specific causes such as traumatic or metabolic nerve injuries, most cases have no clear causative event/injury.11,106 Pain can even be perceived to arise from an amputated, and hence an absent, limb.93,121 Genetic and functional findings have linked voltage-gated sodium channels that are expressed in peripheral sensory neurons to human pain disorders, and support targeting these channels for development of new analgesics.
Nine genes (SCN1A-SCN5A and SCN8A-SCN11A) encode diverse pore-forming sodium channel α-subunits (Nav1.1-Nav1.9) which manifest distinct expression patterns and biophysical and pharmacological properties.24 Sodium channels are composed of 1700 to 2000 amino acids which fold into 4 domains (DI-DIV) with each domain consisting of 6 transmembrane segments, linked by 3 intracellular loops, and cytoplasmic N- and C-termini.23 Adult peripheral sensory neurons can express channels Nav1.1, Nav1.6, and Nav1.7, which are blocked by nanomolar concentrations of the neurotoxin tetrodotoxin (TTX-Sensitive, TTX-S), and channels Nav1.8 and Nav1.9, which are resistant to micromolar concentrations of TTX (TTX-R). The TTX-S channel Nav1.3 is predominantly expressed in embryonic sensory neurons,116 but is up-regulated after traumatic or metabolic nerve injury in rodent dorsal root ganglion (DRG) neurons.35,116 Functional studies of these channels within neurons in which they are normally expressed38 as well as studies in knock-out mice have yielded important information about the contribution of individual sodium channels to electrogenesis within these neurons42,47,97 (Fig. 1).
Three of the channels that are expressed in sensory neurons—Nav1.7, Nav1.8, and Nav1.9—are preferentially expressed in peripheral neurons, whereas Nav1.1 and Nav1.6 are also widely expressed in the central nervous system. Nav1.7 and Nav1.8 channels have garnered intense interest because of the accumulating evidence for their role in human pain disorders and relative ease of studying these channels in isolation in heterologous expression systems or in native neurons.43,57 Evidence for mutations in Nav1.960,61,64,72,73,87,118,127 and Nav1.6108 in human pain conditions has started to appear in the past few years. Recent comprehensive reviews have covered this topic in detail.15,36,37,40,43,57 We provide in this article an overview of the more recent developments that further our understanding of the contribution of peripheral sodium channels to a spectrum of human pain disorders, and the clinical testing of both new and existing sodium channel blockers for treatment of patients carrying mutations in Nav1.7.
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