Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A–11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders. This review provides an overview of the current literature concerning the role of VGSCs in the generation of pain and heritable pain disorders.

INTRODUCTION

Pain perception has an undisputed importance as a survival mechanism in complex organisms. In mammals, the pathways responsible for pain operate at multiple levels of both the peripheral and central nervous system (CNS), under both voluntary and involuntary control. However, pain syndromes of no physiological utility, often induced by physiological responses to nerve damage, chronic inflammation or an underlying genetic component, do not respond to conventional categories of therapeutic analgesics, such as non-steroidal anti-inflammatory and opioids. The genetic and molecular elements underlying these diseases are complex and diverse with up to 400 genes known to be relevant to pain or analgesia [1]. Technological advances in genome sequencing have advanced the past two decades of research into heritable pain syndromes and have significantly contributed to much of our understanding of the transduction and conduction of sensory and nociceptive inputs. Crucially, the importance of voltage-gated sodium channels (VGSCs) in the generation of pain and disease is now well recognized. The present review provides an overview into the current literature concerning VGSCs in the generation of pain disorders.

STRUCTURE AND TISSUE DISTRIBUTION

VGSCs are heteromeric transmembrane protein complexes formed of α and β subunits. Nine homologous members make up the VGSC family whose α subunits are encoded by genes SCN1A–11A. These pore forming α subunits, each composed of a long polypeptide chain (1700–2000 amino acids), comprise four homologous domains (DI–DIV) with each domain broken down into six transmembrane α helical segments (S1–S6). The ion selective pore of the channel is formed by S5–S6 and the voltage sensor is located at S4. Domains are linked by three intracellular loops (L1–L3). Sodium channel isoforms display wide-ranging kinetic properties endowing different neuronal types with distinctly varied firing properties. The association of the α subunits with β auxiliary proteins, encoded by four genes (SCN1B–SCN4B), regulates channel gating and trafficking, allowing cell specific modulation of sodium channels in different cell types. With the exception of Nav1.4, all VGSCs are expressed in the nervous system. The isoforms important in nociceptive transmission and heritable pain disorders, Nav1.7, Nav1.8 and Nav1.9, are all preferentially expressed in the peripheral nervous system (Table 1). Some evidence showing an up-regulation of Nav1.3 in rodent dorsal root ganglia (DRG) neurons following nerve injury has also suggested a potential role for this channel in pain [2]. Nav1.7 is expressed in large and small diameter dorsal root ganglion neurons. Like all three channels, Nav1.7 was first found in somatosensory and sympathetic neurons and has since been detected in myenteric neurons, smooth myocytes, olfactory neurons and visceral sensory neurons. In the CNS, Nav1.7 has been reported in the hypothalamus [3], as well as in free nerve endings within superficial laminae of the dorsal horn in the spinal cord. Previously, the expression of Nav1.8 was thought to be exclusively confined to small and medium diameter nociceptive subsets of sensory neurons of the DRG [4,5]. However it has subsequently been shown that 75% of dorsal root ganglion cells express Nav1.8 with 90% of these expressing nociceptive markers. Evidence also suggests the presence of Nav1.8 in approximately 40% of myelinated A fibres [6]. Furthermore, Nav1.8 has been detected in intracardiac ganglia possibly exerting its effects on cardiac electrophysiological properties [7]. Nav1.9 was first identified in the soma and central terminals of functionally identified nociceptors of the DRG and trigeminal ganglia [8] and is preferentially expressed in small-diameter DRG neurons, trigeminal ganglia neurons and in intrinsic myenteric neurons [9]. The differing properties and cellular localizations of these channels endow different cell types with much of their electrophysiological and functional properties. Nav1.7 produces a rapidly activating and inactivating tetrodotoxin (TTX) sensitive current. This type of channel is well suited to low-frequency firing in C-fibres due to its slow repriming nature [10,11] and is considered a threshold channel due to its ability to boost subthreshold stimuli and thereby increase action potential firing frequency [12,13]. The TTX resistant current produced by Nav1.8 acts as a major contributor to the upstroke of action potentials [14,15]. Under cold conditions, where slow inactivation is enhanced in TTX sensitive channels, Nav1.8 is the sole channel able to generate electrical impulses acting to maintain nociceptor excitability [16]. Nav1.9 has remarkably unique biophysical properties. This channel generates a persistent TTX-resistant current that has very slow gating kinetics and can be activated at potentials close to resting membrane potential [9]. Activation kinetics of this nature are unable to contribute to the up-stroke of action potentials and instead act as modulators of membrane excitability through persistent inward currents and the ability to activate at a strategic range that is negative to, and overlaps with, the voltage thresholds of other transient sodium channels.

Table 1
Expression patterns of VGSCs and their disease association [81]
ChannelGeneTetrodotoxin sensitiveMajor expressionChannel disease association
Nav1.1 SCN1A CNS, PNS, heart Epilepsy, migraine, autism 
Nav1.2 SCN2A CNS, PNS Epilepsy, autism, episodic ataxia 
Nav1.3 SCN3A CNS, PNS Epilepsy 
Nav1.4 SCN4A Skeletal muscle Hyperkalaemic periodic paralysis, paramyotonia congenital, hypokalaemic periodic paralysis 
Nav1.5 SCN5A − Cardiac muscle Brugada syndrome, Long QT syndrome 3, atrial fibrillation 
Nav1.6 SCN8A CNS, ONS, smooth muscle Mental retardation, pancerebellar atrophy, ataxia, infantile experimental encephalopathy 
Nav1.7 SCN9A PNS Congenital insensitivity to pain, inherited primary erythromelalgia, paroxysmal extreme pain disorder, small fibre neuropathy, anosmia 
Nav1.8 SCN10A − PNS, heart Small fibre neuropathy 
Nav1.9 SCN11A − PNS Congenital insensitivity to pain, painful peripheral neuropathy, familial episodic pain syndrome 
NaX SCN7A Circumventricular organs Unknown 
ChannelGeneTetrodotoxin sensitiveMajor expressionChannel disease association
Nav1.1 SCN1A CNS, PNS, heart Epilepsy, migraine, autism 
Nav1.2 SCN2A CNS, PNS Epilepsy, autism, episodic ataxia 
Nav1.3 SCN3A CNS, PNS Epilepsy 
Nav1.4 SCN4A Skeletal muscle Hyperkalaemic periodic paralysis, paramyotonia congenital, hypokalaemic periodic paralysis 
Nav1.5 SCN5A − Cardiac muscle Brugada syndrome, Long QT syndrome 3, atrial fibrillation 
Nav1.6 SCN8A CNS, ONS, smooth muscle Mental retardation, pancerebellar atrophy, ataxia, infantile experimental encephalopathy 
Nav1.7 SCN9A PNS Congenital insensitivity to pain, inherited primary erythromelalgia, paroxysmal extreme pain disorder, small fibre neuropathy, anosmia 
Nav1.8 SCN10A − PNS, heart Small fibre neuropathy 
Nav1.9 SCN11A − PNS Congenital insensitivity to pain, painful peripheral neuropathy, familial episodic pain syndrome 
NaX SCN7A Circumventricular organs Unknown 

Nav1.7 (SCN9A)

Nav1.7 is preferentially expressed in a number of tissues including, DRG, trigeminal ganglia, olfactory epithelia and sympathetic neurons [17,18]. Nav1.7 expression has been recently reported in the hypothalamus [3], as well as in free nerve endings within superficial lamina of the dorsal horn in the spinal cord. Functional mutations in SCN9A are known to be the underlying cause of a number of heritable disorders such as, congenital insensitivity to pain (CIP) [19], inherited primary erythromelalgia (IEM) [20], paroxysmal extreme pain disorder (PEPD) [21] and small fibre neuropathy (SFN) [22].

Several mouse studies have also demonstrated the importance of Nav1.7 in pain sensation, as the conditional knockout of Nav1.7 in Nav1.8 positive nociceptors shows a loss of acute noxious mechanosensation and inflammatory pain [23]. Consistent with human findings, these mice, which lack functional Nav1.7 in the Nav1.8 positive population of sensory neurons, display marked insensitivity to pain and anosmia but are otherwise phenotypically normal [17,18,24]. These mice show no defects in mechanical sensitivity and supraspinal thermal sensitivity (Hargreaves' test). In addition, Nav1.7 knockout mice do not develop formalin-induced inflammatory pain or complete Freund's adjuvant (CFA)-induced thermal hyperalgesia (Table 2). Nav1.7 expression in different sets of mouse sensory and sympathetic neurons are essential for distinct types of pain sensation [22,24]. Deletion of Nav1.7 in all sensory neurons leads to an additional loss of noxious thermosensation [24] (Table 2). Furthermore, although responses to the hotplate, as well as neuropathic pain, are unaffected when SCN9A is deleted in all sensory neurons, in mice the ablation of Nav1.7 in all DRG sensory neurons and sympathetic neurons, shows a significant reduction in thermal sensitivity in the hotplate test and mechanical hypersensitivity in a surgical neuropathic pain model [24] (Table 2). These studies indicate the importance of Nav1.7 in pain sensation and highlight it as an ideal drug target for pain therapies.

Table 2
A summary of pain behaviour in Nav1.7, Nav1.8 and Nav1.9 KO mice (0: no change, −: reduced responses)

Nav1.7Nav1.8: Nav1.7 floxed Nav1.8-Cre (Nav1.7 is deleted in Nav1.8-positive sensory neurons), Nav1.7Advillin: Nav1.7floxed Advillin-Cre (Nav1.7 is deleted in all sensory neurons), Nav1.7Wnt1: Nav1.7 floxed Wnt1-Cre (Nav1.7 is deleted in all sensory neurons and sympathetic neurons), Nav1.8DTA: floxed stop DTA Nav1.8-Cre (Nav1.8-positive neurons are ablated with diphtheria toxin). Mechanical pain: Randall–Selitto test (RS), light touch: Von Frey (vF), thermal spinal reflex: Hargreaves’ test (HG), supraspinal thermal: hot plate test, noxious cold: cold plate test, noxious cooling: acetone test, weight distribution to each hindpaw: weight-bearing test (WB). SNT, spinal nerve transection; CCI, chronic constriction injury; SNI, spared nerve injury.

Acute painInflammatory pain (F: formalin, C; carrageenan)Neuropathic pain
Transgenic miceRSvFHGHot plateCold plateAcetoneFCFACOtherSNTCCISNIReference
Nav1.7 KO − (tail-clip) − −   − − (HG)      [24
Nav1.7Nav1.8 − 0/− − − − (HG, vF) − (HG)     [22,23
Nav1.7Advillin − − −     0 (vF)   [24
Nav1.7Wnt1 − − − −     − (vF)   [24
Nav1.8 KO − 0/−   − (HG), 0 (vF) 0/− (HG)   0 (vF) 0 (vF) [13,75
Nav1.8DTA − −  0/− − (vF, HG) In supplementary info  0 (vF, HG)   [13,15,74
Nav1.9 KO   − − (Hot plate, warm water, WB), 0 (vF),−/0 (HG) −(vF, warm water, WB), −/0 (HG) − (PGE2, NGF, IL-1β, bradykinin; vF, Hot plate)  0 (vF, WB), − (acetone) 0 (vF, WB, acetone) [7578
Acute painInflammatory pain (F: formalin, C; carrageenan)Neuropathic pain
Transgenic miceRSvFHGHot plateCold plateAcetoneFCFACOtherSNTCCISNIReference
Nav1.7 KO − (tail-clip) − −   − − (HG)      [24
Nav1.7Nav1.8 − 0/− − − − (HG, vF) − (HG)     [22,23
Nav1.7Advillin − − −     0 (vF)   [24
Nav1.7Wnt1 − − − −     − (vF)   [24
Nav1.8 KO − 0/−   − (HG), 0 (vF) 0/− (HG)   0 (vF) 0 (vF) [13,75
Nav1.8DTA − −  0/− − (vF, HG) In supplementary info  0 (vF, HG)   [13,15,74
Nav1.9 KO   − − (Hot plate, warm water, WB), 0 (vF),−/0 (HG) −(vF, warm water, WB), −/0 (HG) − (PGE2, NGF, IL-1β, bradykinin; vF, Hot plate)  0 (vF, WB), − (acetone) 0 (vF, WB, acetone) [7578

Considerable efforts have been made to develop new analgesic drugs which selectively block Nav1.7 [25]. Moreover, a recent study focusing on the natural antisense transcript (NAT) for SCN9A [26], that is conserved in humans and mice, showed it can down-regulate Nav1.7 mRNA and protein levels and reduce Nav1.7 peak sodium currents in human embryonic kidney cells (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines. These results suggest that the SCN9A NAT can attenuate native sodium currents and regulate SCN9A post-transcriptionally, which can potentially alter pain thresholds, leading to a potential candidate for new therapies.

Aside from the generation and propagation of action potentials in sensory neurons, further functional roles for Nav1.7 have been uncovered such as, the involvement of Nav1.7 in itch [27,28] and neurotransmitter release [18,24,2729]. In the olfactory system, deleting Nav1.7 in all olfactory sensory neurons leads to an absence of postsynaptic responses and currents in olfactory bulb projection neurons. However, these neurons produce normal action potentials when depolarized via current injection through the patch pipette, which may therefore involve Nav1.7 in neurotransmitter release [18]. Other groups have also reported that electrical stimulation of isolated sciatic nerve roots failed to induce increased substance P release in the dorsal horn of conditional Nav1.7 KO mice, where Nav1.7 was deleted in all sensory neurons [24].

Nav1.8 (SCN10A)

Nav1.8 is expressed in small diameter unmyelinated nociceptive sensory neurons [4]. The predominant sodium conductance generated by Nav1.8 in small neurons (18–25 μm diameter) is resistant to TTX and slower than in many larger DRG neurons (44–50 μm diameter), whereas sodium conductance in the large neurons is kinetically faster and TTX sensitive [30]. This TTX-resistant sodium channel (IC50=60 μM) [14,23], is the main contributor to the upstroke phase of action potentials in nociceptive neurons [14,15]. Nav1.8 also mediates the excitability of nociceptors at low temperatures, and is therefore an essential component in the propagation of cold stimuli [16]. In mice, deleting Nav1.8 in sensory neurons reduces the sensitivity to noxious mechanical stimuli, thermal stimuli and causes insensitivity to noxious cold [13,15,74] (Table 2). Engineered gain-of-function mutations in SCN10A in mice increase sensitivity to cold stimuli by enhancing Nav1.8 sodium currents, as well as mechanically evoked action potential firing in subclasses of Aβ, Aδ and C-fibres [31,32]. This evidence cumulatively supports the role of Nav1.8 in cold stimuli and painful neuropathies in human studies.

Multiple studies also support the role of Nav1.8 in inflammatory pain; Nav1.8 KO mice show reduced CFA-induced heat hypersensitivity [75], and deletion of Nav1.8-expression neurons in sensory ganglia using diphtheria toxin reduces mechanical and heat hypersensitivity in carrageenan and CFA models [74] (Table 2). Furthermore, the administration of antisense oligodeoxynucleotides in rats leads to a decrease in prostaglandin E2 (PGE2)-induced hyperalgesia [33] and reverses (CFA)-induced heat and mechanical hypersensitivity [34]. In contrast, the role of Nav1.8 in neuropathic pain is unclear. In some antisense studies, knockdown of Nav1.8 attenuates the development and maintenance of neuropathic pain in rats [35,36]. On the other hand, Nav1.8 knockout mice, as well as Nav1.7 and Nav1.8 double knockout mice, show normal behaviour in neuropathic pain models [36,37,75] (Table 2).

In humans, gain-of-function of mutations in Nav1.8 patients with small fibre neuropathies underlie mechanical hypersensitivity [29,61]. Electrophysiology studies using Nav1.8-null mouse DRG neurons, transfected with either Nav1.8 WT or mutant constructs, have demonstrated that these mutations cause increased excitability of small DRG neurons characterized as nociceptors. These neurons have reduced current threshold, increased firing frequency and increased spontaneous firing [29,61]. A recent electrophysiological study has provided novel distinctions between properties of the human and rodent Nav1.8 orthologues, including slower inactivation kinetics, larger persistent and ramp currents, as well as longer-lasting action potentials and increased firing frequency in human Nav1.8 channels [80].

Nav1.9 (SCN11A)

Nav1.9 is expressed in nociceptive DRG, trigeminal ganglia and motor neurons [8]. SCN11A encodes a 1765 amino acid protein that shows the least degree of homology to other members of the neuronal VGSC family [41]. Because this TTX-resistant channel activates at more hyperpolarizing voltages in comparison with other VGSCs, which produces its characteristic persistent current, Nav1.9 regulates resting membrane potentials and prolongs the depolarization response to subthreshold stimuli [42,43] that lower the threshold for single action potentials and increasing repetitive firing [44].

Nav1.9 plays an important role in the generation of inflammatory pain (Table 2). Rodent DRG neurons treated with inflammatory mediators, including interleukin-1B, bradykinin and PGE2, show increased current density of the channel, lowering the threshold for action potential generation in these neurons and ultimately enhancing excitability [4547]. Nav1.9 knockout mice show reduced inflammatory responses compared with wild type [7578] (Table 2). These mice do not develop thermal hyperalgesia after CFA [7678] or carrageenan injection [76] (Table 2). Mechanical hypersensitivity induced by CFA- and formalin-induced inflammation is also diminished in Nav1.9 knockouts [75,76,78] (Table 2).

A number of rare mutations in the SCN11A gene have been reported to underlie pain disorders. Familial episodic pain [48] is caused by two missense mutations in Nav1.9 that reduce the threshold for action potential generation and increase firing frequency without changing the resting membrane potential. Furthermore, a mutation in the domain II S4–S5 linker region of the channel (G699R) is associated with a subtype of painful SFN. By causing a hyperpolarization in channel activation and a depolarization in steady-state fast inactivation along with enhancing ramp responses of Nav1.9, this mutation leads to a hyperexcitability in dorsal root ganglion neurons via the maintenance of a depolarized resting membrane potential [49]. Other gain-of-function mutations in this channel include another subtype of peripheral neuropathy [50] and heritable pain insensitivity [51].

HUMAN HERITABLE SODIUM CHANNELOPATHIES

Inherited primary erythromelalgia (Nav1.7)

Mutations in SCN9A underlie IEM. Symptoms of this gain-of-function disease include symmetrical burning pain accompanied by redness, increased skin temperature, oedema and erythema. Symptoms usually appear in childhood or adolescence and the phenotype can vary from mild to severe, even within the same family. The first IEM-related mutations were identified in a Chinese family in 2004 [20] and more have been reported since [52,53]. Electrophysiological characterizations of IEM-related mutations in SCN9A demonstrate a hyperpolarizing shift in the voltage-dependence activation and increased persistent current of the channel [52]. Recent studies have also suggested that these mutations lead to a significant hyperpolarized shift in voltage-dependent activation [79], and a persistent current, which in turn, leads to a reduced current threshold and enhanced action potential firing probability [54]. Furthermore, along with the notable expression of Nav1.7 in sensory neurons, sympathetic ganglion neurons, and olfactory neurons, expression of Nav1.9 in smooth muscle cells of cutaneous arterioles, arteriole–venule shunts and endothelial cells in the skin may also account for skin redness seen in IEM patients [55]. However, despite the evidence supporting SCN9A mutations in IEM, only 10% of IEM families are proven to have SCN9A mutations, implying that some other genetic mutations may be linked to this disorder [56].

Paroxysmal extreme pain disorder (Nav1.7)

PEPD (originally termed familial rectal pain syndrome) is a dominant heritable condition with the most common symptom involving severe burning pain in the rectal, ocular and submandibular areas, with episodes lasting up to several hours. Pain attacks can also be accompanied by flushing of the skin, legs, eyelid and buttocks [21,57]. In 2006 Fertleman and colleagues described the first mutations associated with PEPD. The eight disease-causing mutations in SCN9A were mapped in 11 families and 2 sporadic cases [21]. Electrophysiological analyses showed that gain-of-function mutations in SCN9A are linked to this disorder. Although, both IEM and PEPD are caused by gain-of-function mutations in SCN9A, their electrophysiological profiles are distinct. In contrast with IEM, certain PEPD mutations shift the voltage dependency of steady-state fast-inactivation in a depolarizing direction, thereby increasing the probability of incomplete inactivation and resulting in a persistent current after activation. Interestingly, one SCN9A mutation is associated with a mixed clinical phenotype, displaying characteristics of both IEM and PEPD [58].

Pain insensitivity (Nav1.7 and Nav1.9)

Two genes encoding VGSCs have been associated with pain insensitivity, namely SCN9A and SCN11A. The first description of homozygous nonsense mutations in SCN9A causing a CIP phenotype was described in a number of patients originating from consanguineous families in northern Pakistan [19]. Since this discovery, the same loss-of-function mutations in SCN9A causing pain insensitivity have been reported in other families [59,60]. However, a recent electrophysiological study has revealed that three CIP-associated mutations in Nav1.7 retained some channel functions but that all mutations demonstrated a significant reduction in peak current following activation and changes in activation and/or inactivation properties. Two C-terminal mutations (W1775R and L1831X) showed a depolarizing shift in channel activation; the other mutation (A1236E, location: D3/S2) and one of the C-terminal mutations (L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation [61]. Further studies in vivo are needed to investigate the link between these mutations and the CIP phenotype, but it seems likely that these mutations lead to a loss of function in vivo. Another phenotype caused by loss-of-function mutations in exon 22 of SCN9A was described in 2013 in two Japanese families [62]. In contrast with the Pakistani families, these patients demonstrated complete loss of temperature sensation, autonomic nervous dysfunctions, hearing loss and hyposmia in addition to adolescent onset loss of pain. The reason for the underlying differences in the sensory phenotypes in these individuals remains elusive.

Interestingly, pain insensitivity phenotypes are not solely generated by mutations confined to SCN9A. In 2013, a de novo missense mutations in SCN11A was found in two patients exhibiting a CIP phenotype [51]. These individuals displayed signs of mild muscular weakness, delayed motor development, slightly reduced motor and sensory nerve conduction velocities with normal amplitudes, no intellectual disability and a prominent hyperhidrosis together with gastrointestinal dysfunction. A mutation changing a highly conserved amino acid within the D2/S6 was identified in these patients and an investigation into the electrical properties of mouse DRG neurons suggested a gain-of-function mutation in this channel is the underlying cause of this pain insensitive phenotype. Loss of Nav1.9 channel in knockout mice had a minor effect on the electrical activity of DRG neurons [51].

Small fibre neuropathies/painful peripheral neuropathies (Nav1.7, Nav1.8 and Nav1.9)

Adult-onset SFN affects unmyelinated and thin myelinated axons and leads to a reduced intraepidermal nerve fibre density. This disorder is often characterized by burning pain, allodynia and hyperesthesia. Large diameter axons are not damaged by SFN, resulting in normal tendon reflexes and vibration sense, and preservation of normal nerve conduction.

SCN9A, SCN10A, SCN11A have been identified as the three VGSC encoding genes which correlate with SFN. Gain-of-function missense variants in SCN9A have been reported in approximately one-third of the individuals with small fibre neuropathies [63]. The phenotype of these individuals with SCN9A mutations is different from IEM. For instance, SFN patients have reported experiencing pain throughout the body, whereas in IEM pain tends to localize to the extremities. Furthermore, neither heat nor cold trigger symptoms in SFN patients, in contrast to patients with IEM [63]. Functional profiling of the SFN mutant Nav1.7 channels showed impaired slow inactivation, depolarized slow and fast inactivation and increased resurgent currents. However, the hyperpolarizing shift in voltage dependence of activation and enhanced ramp responses that normally characterize IEM were not observed. In addition, the SFN mutant Nav1.7 channels did not demonstrate the incomplete fast inactivation often found in PEPD [63].

Gain-of-function mutations in Nav1.8 have also been identified in patients with painful SFN [40]. These mutations caused enhanced ramp responses, recovery from inactivation and activation, and led to hyperexcitability of small neurons in DRG, characterized by reduced current threshold, increased firing frequency and an increase in spontaneous activity.

More recently, mutations in SCN11A have been identified as a cause of painful peripheral neuropathy (PPN) [64]. From a cohort of 393 patients, diagnosed with SFN, the gene SCN11A was sequenced from patients of this cohort who did not have mutations in SCN9A and SCN10A. From this cohort of 345 patients, eight variants were found in 12 patients. Functional analysis showed the mutations depolarize resting membrane potential of DRG, enhance spontaneous firing and increase evoked firing, indicating that gain-of-function mutations in Nav1.9 can cause PPN.

Familial episodic pain syndrome (Nav1.9)

Familial episodic pain syndrome (FEP) is a Mendelian heritable trait resulting in severe pain and is triggered by conditions such as fatigue, fasting and cold. Three distinct types of this disease have so far been documented. Type I, characterized by pain localized predominantly to the upper body, is linked to a gain-of-function missense mutation in TRPA1 [64]. This is in contrast with the autosomal dominant type III disease form, first identified in two Chinese families, which is characterized by pain in the distal parts of the body, more specifically localized to the hands and feet [48]. In these patients, pain attacks usually occur late in the day with pain expanding simultaneously in different localizations, often triggered by intercurrent illness and fatigue after exercise. A combination of linkage analysis and whole-exome sequencing in both Chinese families has revealed missense mutations in SCN11A. Electrophysiological analysis has shown these mutations cause hyperexcitability of DRG neurons with increased peak current densities and enhanced action potential firing after current injection (Figure 1 and Table 3).

VGSC function and disease association

Figure 1
VGSC function and disease association

Schematic of a typical VGSC. VGSCs are heteromeric transmembrane proteins complexes. Nine homologous members, SCN1A–11A, make up the VGSC gene family. The pore forming α subunit encoded by these genes is comprised of four homologous domains (DI–DIV). Each domain can be broken down into six transmembrane α helix segments (S1–S6) with the voltage sensor located at S4. The pore is formed by S5–S6. Numbered red dots designate the location of currently known mutations associated with major pain diseases summarized in Table 3. 

Figure 1
VGSC function and disease association

Schematic of a typical VGSC. VGSCs are heteromeric transmembrane proteins complexes. Nine homologous members, SCN1A–11A, make up the VGSC gene family. The pore forming α subunit encoded by these genes is comprised of four homologous domains (DI–DIV). Each domain can be broken down into six transmembrane α helix segments (S1–S6) with the voltage sensor located at S4. The pore is formed by S5–S6. Numbered red dots designate the location of currently known mutations associated with major pain diseases summarized in Table 3. 

Table 3
VGSCs channelopathies and mutations
No. in Figure 1 VGSCsProtein mutationDiseaseFunctional effectReference
Nav1.7 S459X CIP Loss-of-function [3
Nav1.7 I767X CIP Loss-of-function [3
Nav1.7 W897 CIP Loss-of-function [3
Nav1.7 L1331P CIP Loss-of-function [35
Nav1.7 I848T/ L858H IEM Gain-of-function [4
Nav1.7 M1627K PEPD Gain-of-function [5
Nav1.7 I1461T/T1464I PEPD Gain-of-function [5
Nav1.7 A1632E IEM/PEPD Gain-of-function [31
Nav1.8 L544P SFN Gain-of-function [16
10 Nav1.8 A1304T SFN Gain-of-function [16
11 Nav1.9 L811P CIP Gain-of-function [36
12 Nav1.9 R255C FEP Gain-of-function [40
13 Nav1.9 A808G FEP Gain-of-function [40
14 Nav1.9 I381T PPN Gain-of-function [38
15 Nav1.9 L1158P PPN Gain-of-function [38
16 Nav1.9 G699R SFN Gain-of-function [46
No. in Figure 1 VGSCsProtein mutationDiseaseFunctional effectReference
Nav1.7 S459X CIP Loss-of-function [3
Nav1.7 I767X CIP Loss-of-function [3
Nav1.7 W897 CIP Loss-of-function [3
Nav1.7 L1331P CIP Loss-of-function [35
Nav1.7 I848T/ L858H IEM Gain-of-function [4
Nav1.7 M1627K PEPD Gain-of-function [5
Nav1.7 I1461T/T1464I PEPD Gain-of-function [5
Nav1.7 A1632E IEM/PEPD Gain-of-function [31
Nav1.8 L544P SFN Gain-of-function [16
10 Nav1.8 A1304T SFN Gain-of-function [16
11 Nav1.9 L811P CIP Gain-of-function [36
12 Nav1.9 R255C FEP Gain-of-function [40
13 Nav1.9 A808G FEP Gain-of-function [40
14 Nav1.9 I381T PPN Gain-of-function [38
15 Nav1.9 L1158P PPN Gain-of-function [38
16 Nav1.9 G699R SFN Gain-of-function [46

THE ENIGMA OF NAV1.7

Nav1.7 plays an integral part in the electrical excitability of nociceptive neurons. Its selective role in nociception and the lack of cognitive and cardiac adverse effects in individuals with non-functional Nav1.7 (CIP and Nav1.7 knockout mice models) has fuelled efforts to develop Nav1.7- specific blockers for the treatment of pain. However, despite some reports outlining restricted efficacy of Nav1.7 channels blockers in animal models of pain [6567], in vitro experiments [68], and the occasional IEM patient responding to monotherapy using pan-sodium channel blockers [69,70], progress in this field of therapeutic development has been slow with marginal progress [71]. The lack of potent analgesia from efficient Nav1.7 blockers suggests a more complex involvement for this channel in the generation of pain aside from electrical conduction. Indeed, in a recent study the deletion of Nav1.7 in mouse sensory neurons of the DRG was shown to provoke an important dysregulation in a number of genes (194 genes >1.5-fold dysregulated) including an up-regulation in the gene encoding the pro-enkephalin Penk, a well-characterized endogenous opioid [72,73]. Furthermore, the administration of naloxone into a human CIP individual with two mutations in SCN9A, and injection into Nav1.7-null mutant mice, reversed endogenous analgesia. This change in expression of endogenous opioid peptides could explain the CIP phenotype in Nav1.7 null mutant mice and non-functional Nav1.7 in humans, also introducing a level of complexity in the role of Nav1.7 and/or sodium, associated with transcriptional regulation. Indeed, the association between transcription and ion channels is well documented in the case of the closely related VGSCs [74,75]. These multiple functionalities of Nav1.7 offer insight into the lack of effectiveness of pharmaceutical blockers [25,76], suggesting that a more efficient approach to producing potent analgesia through Nav1.7 would be a synergistic combination involving sodium channel blockers and opioids.

CONCLUSION

The last decade's research into the nature of heritable pain-related diseases and pain conduction has shed a great deal of light on to the functional roles of VGSCs in pain neurotransmission and sensory conduction as a whole. The more recent evidence indicating a role for these channels in transcription and neurotransmitter release has pointed to yet more potential for these channels to be used in the development of analgesic drugs.

We would like to thank Prof John N. Wood for his help in the preparation of this review and to Dr. Jane Sexton and Dr. Shafaq Sikandar for proofreading.

Abbreviations

     
  • CFA

    complete Freund's adjuvant

  •  
  • CIP

    congenital insensitivity to pain

  •  
  • CNS

    central nervous system

  •  
  • DRG

    dorsal root ganglia

  •  
  • FEP

    familial episodic pain syndrome

  •  
  • IEM

    inherited primary erythromelalgia

  •  
  • NAT

    natural antisense transcript

  •  
  • PEPD

    paroxysmal extreme pain disorder

  •  
  • PGE2

    prostaglandin E2

  •  
  • PPN

    painful peripheral neuropathy

  •  
  • SFN

    small fibre neuropathy

  •  
  • TTX

    tetrodotoxin

  •  
  • VGSC

    voltage-gated sodium channel

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Author notes

1

Both authors have contributed equally to the manuscript.