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date: 22 January 2019

Sodium Channels and Pain

Abstract and Keywords

Electrical excitability in nerve and muscle depends on the action of voltage-gated sodium-selective ion channels. It is now known that there are nine such ion channels; intriguingly, three of them, Nav1.7, Nav1.8, and Nav1.9, are found relatively selectively in peripheral damage-sensing neurons. Local anesthetics are sodium channel blockers that have proved to be excellent analgesics. However, their systemic use is limited by side effects. Because it is known that peripheral damage-sensing sensory neurons are required to drive most pain conditions, there have been many attempts to target peripheral sodium channels for pain relief. Human genetic advances have supported the idea that multiple sodium channel subtypes are good analgesic drug targets. Human monogenic gain-of-function mutations in Nav1.7, Nav1.8, and Nav1.9 cause ongoing pain conditions, while loss-of-function Nav1.7 mutations produce insensitivity to pain. This compelling genetic evidence has inspired a large number of drug development programs aimed at developing analgesic subtype-selective sodium channel blockers. This chapter overviews the structure and physiological role of voltage-gated sodium channels and describes recent advances in understanding the contribution of sodium channel isoforms to different pain states. Also described are mechanistic studies aimed at better understanding routes to drug development and the potential of gene therapy in therapeutic approaches to pain control. Two decades of sodium channel–targeted drug development have yet to produce a clinical breakthrough, but recent progress holds promise that useful new analgesics are on the horizon.

Keywords: ion channel, pain, action potential, electrical excitability, local anesthetics, subtype selective blockers, analgesic drugs

Introduction

The development of lidocaine as a long-lasting local anesthetic by Swedish scientists in the 1940s revolutionized surgical procedures, although use of the drug as an analgesic began a decade later (Chong et al., 1995; Holmdahl, 1998; Ketelslegers, 1952). The locus of action on voltage-gated sodium channels was appreciated more recently. The demonstration that pain can be blocked by silencing peripheral nerves highlighted peripheral sodium channels as useful analgesic drug targets (S. D. Dib-Hajj, Geha, & Waxman, 2017). The present consensus view of pain mechanisms is that peripheral drive into the central nervous system plays a key role in the vast majority of pain conditions, so sensory neuron voltage-gated sodium channels are obvious targets to treat pain (Waxman et al., 2014). The most common systemically applied local anesthetics are effective drugs in treating not only acute but also neuropathic pain in controlled clinical studies (Challapalli, Tremont-Lukats, McNicol, Lau, & Carr, 2005). This chapter highlights the role of sodium channel isoforms in pain mechanisms and describes recent progress in the development of sodium channel–targeted analgesic strategies.

Structure and Accessory Subunits

The primary functional unit of voltage-gated sodium channels in eukaryotes is a 220- to 260-kDa polypeptide, referred to as the alpha subunit. The first voltage-gated sodium channel alpha subunit cloned was the eel electroplax sodium channel (Noda et al., 1984). Biochemical analyses demonstrated that the eel electroplax channel consisted of a single large alpha subunit (Agnew, Levinson, Brabson, & Raftery, 1978). Voltage-gated sodium channel alpha subunits have been cloned from numerous species, including human, rat, rabbit, drosophila, squid, jellyfish, and bacteria. In mammals, nine voltage-gated sodium channel genes coding for nine major isoforms (Table 1) have been identified (Goldin et al., 2000). A tenth isoform, Nax, has a similar structure but is not likely to be voltage gated. NaV1.3, NaV1.6, NaV1.7, NaV1.8, and NaV1.9 have the strongest documented links to pain, but all of the mammalian isoforms have been implicated in altered pain sensations to some degree. All of the mammalian alpha-subunit variants also have the same basic overall structure as originally described for the eel channel, with 24 transmembrane segments arranged in four pseudosubunits or domains (DI–DIV) (Figure 1). Each domain consists of six transmembrane segments (S1–S6) and a pore loop (SS1–SS2 regions).

Table 1. Mammalian Voltage-Gated Sodium Channels

Channel

Gene

Human Chromosomal Location

Tissue Distribution

Tetrodotoxin-Sensitivity Properties

Nav1.1

SCN1A

2q24.3

DRG, TG, CNS

TTX-S

Nav1.2

SCN2A

2q24.3

CNS

TTX-S

Nav1.3

SCN3A

2q24.3

Fetal DRG, CNS

TTX-S

Nav1.4

SCN4A

17q23.3

Skeletal muscle

TTX-S

Nav1.5

SCN5A

3p22.2

Heart

TTX-R

Nav1.6

SCN8A

12q13.13

DRG, TG, CNS

TTX-S

Nav1.7

SCN9A

2q24.3

DRG, TG, SCG

TTX-S

Nav1.8

SCN10A

3p22.2

DRG, TG

TTX-R

Nav1.9

SCN11A

3p22.2

DRG, TG

TTX-R

Nax

SCN7A

2q24.3

Enteric, lung, nerve

ND

CNS = central nervous system; DRG = dorsal root ganglion; ND = not determined; TG = trigeminal ganglia; TTX-R = tetrodotoxin resistant; TTX-S = tetrodotoxin sensitive; SCG = superior cervical ganglion.

Sodium Channels and PainClick to view larger

Figure 1. Secondary structure of mammalian voltage-gated sodium channel. The inactivation particle in the DIII–DIV loop is shown by the boxed IFM. S4 voltage-sensing segments are indicated in orange.

A phylogenetic analysis of 277 four-domain, voltage-gated cation channels concluded that the ancestor of eukaryotic voltage-gated sodium channels is a four-domain, voltage-gated calcium channel (Figure 2) (Pozdnyakov, Matantseva, & Skarlato, 2018). The pore loops of the four domains in eukaryotic sodium and calcium channels extend partway into the plane of the lipid bilayer from the extracellular side of the membrane and form both the large outer vestibule of the pore and the narrow central pore restriction that constitutes the selectivity filter.

Sodium Channels and PainClick to view larger

Figure 2. Three-dimensional structure of a four-domain, voltage-gated sodium channel. (A) Side view of the Nav1.4 sodium channel from the electric eel. (B) Bottom-up view from the cytoplasmic face of the eel Nav1.4. Structures adapted from PDB ID code 5X5Y (Yan et al., 2017).

In calcium channels, the selectivity filter depends on four glutamate residues, whereas in sodium channels, it is formed by aspartate, glutamate, lysine, and alanine (one from each of the four domains). This DEKA motif permits permeation of sodium ions preferentially over other cations, including calcium and potassium. This outer pore region of voltage-gated sodium channels is targeted by multiple pore-blocking toxins, including tetrodotoxin (TTX) and some conotoxins (Cestele & Catterall, 2000). TTX sensitivity has been used to differentiate the properties and contributions of voltage-gated sodium channels, especially those expressed in nociceptive neurons (Akopian, Sivilotti, & Wood, 1996; Roy & Narahashi, 1992).

The S5 and S6 segments of each domain form a funnel-like structure, with the wide end constraining the outer pore formed by the pore loops and the inner portion of the S6 segments forming the inner pore. A high-resolution structure of the eel electroplax voltage-gated sodium channel confirms this arrangement (Yan et al., 2017) and supports the proposal that the S6 tetrahelical bundle undergoes an iris-like constriction at negative potentials to block (or gate) the sodium flux through the channel. At depolarized potentials, this bundle is relaxed, opening the pore and allowing sodium to conduct. Lidocaine and many other clinically relevant sodium channel blockers bind to S6 residues lining the inner pore (Ragsdale, McPhee, Scheuer, & Catterall, 1996).

The alpha subunits are subjected to extensive post-translation modifications (Pei, Pan, & Cummins, 2018), including glycosylation of outer residues and phosphorylation of residues on intracellular regions (Laedermann, Abriel, & Decosterd, 2015). The major intracellular regions, the N- and C-termini as well as the DI–II, DII–III, and DIII–IV linkers, are all subject to post-translation modifications, although the DI–II linker appears to be a hotspot for phosphorylation (Ashpole et al., 2012; Fitzgerald, Okuse, Wood, Dolphin, & Moss, 1999; Wittmack, Rush, Hudmon, Waxman, & Dib-Hajj, 2005). Interestingly, the NaV1.4 and NaV1.9 isoforms are different from the other mammalian variants in that their DI–DII linkers are about 200 amino acids shorter (S. D. Dib-Hajj, Tyrrell, Black, & Waxman, 1998).

While the alpha subunit is typically sufficient for generating sodium conductance across the plasma membrane, mammalian channels are most often associated with one or more beta subunits. Four distinct beta subunits that contain a single transmembrane segment and associate with the alpha subunits have been identified (Brackenbury & Isom, 2011). These are likely to be important in trafficking, localization, and gating behaviors of the alpha subunits, although it is not clear which beta subunits interact with which specific alpha subunits in different cells.

Numerous other proteins are associated with sodium channels and can modulate their functional properties. A recent study identified 267 proteins that interacted in vivo with an epitope-tagged NaV1.7 using gene-targeted mice (Kanellopoulos et al., 2018), raising new questions about the complexity of voltage-gated sodium channels.

Transcriptional Control of Sodium Channel Expression

The cell-specific expression of sodium channels is controlled transcriptionally, while post-translational functional changes play an important role in regulating the activity and neuronal excitability of different isoforms (Pei et al., 2018). The human genomic loci encoding channels NaV1.1, NaV1.2, NaV1.3, NaV1.7, and Nax are all found on chromosome 2; the TTX-resistant channels NaV1.5, NaV1.8, and NaV1.9 are clustered on chromosome 3. The muscle channel NaV1.4 is found on chromosome 17.

A key regulatory sequence upstream of sodium channel genes found in the nervous system also defines neuron-specific expression of many other genes (Chong et al., 1995; Lu, Ikeda, & Puhl, 2015; Mori, Schoenherr, Vandenbergh, & Anderson, 1992; Schoenherr & Anderson, 1995). The neuron-restricted silencing element (NRSE), or REST, is a 21-bp sequence that restricts gene expression to neuronal cells through the action of a transcriptional repressor that shuts down gene expression in nonneuronal cells. Positive elements regulating sodium channel expression have proved more elusive. Upstream sequences that confer the exquisite sensory neuron–specific pattern of expression of NaV1.8 have been mapped (Puhl & Ikeda, 2008).

Interestingly, a regulatory enhancer element controlling expression of the heart channel NaV1.5 is found within the genomic locus of NaV1.8 (van den Boogaard et al., 2014). When this sequence is deleted in mice, the level of NaV1.5 messenger RNA (mRNA) falls markedly, and the same region regulates NaV1.5 expression in humans, with effects on cardiac conduction.

More recently, an antisense RNA transcript overlapping with NaV1.7 has been identified and its function explored in terms of channel expression (Koenig et al., 2015). Large-scale transcriptomic studies of sensory neurons as well as in situ studies have given a good view of the pattern of expression of sodium channels in sensory ganglia (Usoskin et al., 2015). Interestingly, there are rostrocaudal differences in sodium channel expression: NaV1.8 is more highly expressed in sacral rather than lumbar mouse dorsal root ganglia (DRG), for example (Minett, Eijkelkamp, & Wood, 2014).

Biophysical Properties of Voltage-Gated Sodium Channels

The primary functional role of voltage-gated sodium channels is to initiate and regulate action potential activity in excitable cells such as muscle and neurons. Voltage-gated sodium channels exhibit complex conformational changes that impact their conductance of sodium ions, and these changes are often referred to as sodium channel gating. The gating of sodium channel isoforms, especially those expressed in nociceptive neurons, can be quite distinctive. Hodgkin and Huxley determined the fundamental contributions of sodium currents to squid action potentials in their landmark papers published in 1952 (Hodgkin & Huxley, 1952a, 1952c, 1952d). They showed that voltage-gated sodium currents are exquisitely sensitive to small changes in membrane potential and the movement of charged particles within the membrane in response to these changes. In sodium and calcium channels, each domain has positively charged residues at roughly every third position in the S4. Charge mutations in the S4 segments alter the voltage dependence of activation and can alter the sensitivity to voltage changes (Bezanilla, 2000). Although the total number of charged residues in each of the four voltage-gated sodium channel domains varies from four to seven, this distribution is highly conserved among the nine mammalian isoforms (with the exception of the DIII-S4 in NaV1.9, which has one fewer positive charge). Surprisingly, the voltage dependence of the mammalian sodium channel isoforms can differ by tens of millivolts.

In their mathematical model of the squid action potential, Hodgkin and Huxley proposed that the opening of the voltage-gated sodium conductance depended on three activation gates (Hodgkin & Huxley, 1952d). Interestingly, while the activation properties of most voltage-gated sodium currents can be modeled with three activation gates, the currents generated by NaV1.9 channels are best modeled with a single activation gate (Herzog, Cummins, & Waxman, 2001). Activation of NaV1.9 channels is also typically ten-fold slower than that of other voltage-gated sodium channels (Cummins et al., 1999). These observations suggest that a single conformational transition dominates NaV1.9 activation kinetics, although it is not clear what the precise underlying molecular mechanism is for this.

Hodgkin and Huxley also described a fast inactivation process for voltage-gated sodium conductances as a crucial element of action potential generation (Hodgkin & Huxley, 1952b). Fast inactivation was proposed as a separate voltage-dependent process, with its own intrinsic voltage-dependent gate that shuts off the flux of sodium conductance via an inactivation particle. This independent fast inactivation gate is crucial for the generation of refractory periods in neurons and other excitable cells.

Armstrong and Bezanilla (Bezanilla & Armstrong, 1977) proposed what is known as the “ball-and-chain” model for inactivation. West et al. (1992) identified a cluster of three hydrophobic amino acids in the III–IV linker that appear crucial to fast inactivation, known as the isoleucine-phenylalanine-methionine (IFM) inactivation particle, and proposed a hinged-lid mechanism involving the III–IV linker. Although the III–IV linker is highly conserved among the nine isoforms, fast inactivation properties differ to a greater extent than activation.

The DIV voltage sensor plays a key role in inactivation (Chahine et al., 1994), and selectively trapping the DIV voltage sensor in the closed position blocks inactivation but does not prevent activation (Xiao, Blumenthal, & Cummins, 2014). Fast inactivation in sodium channels can occur from both the closed and open states (Aldrich & Stevens, 1987; Groome, Lehmann-Horn, & Holzherr, 2011). The high-resolution cryoelectron microscopy structure of the electric eel voltage-gated sodium channel indicates that the IFM particle binds to a region outside the central pore pathway and induces inactivation via an allosteric mechanism rather than by direct pore blockade (Yan et al., 2017). However, it is unclear if the resolved structure captured a closed-inactivated state or an open-inactivated state.

Sodium currents in peripheral sensory neurons, especially nociceptive neurons, display multiple inactivation time constants, with fast, slow, and persistent voltage-gated sodium current components (Cummins et al., 1999; Roy & Narahashi, 1992). Although NaV1.9 is the major generator of persistent currents in nociceptive neurons, persistent currents can be associated with other isoforms (Crill, 1996). Incomplete or impaired inactivation can result in persistent sodium currents. Enhanced overlap between the voltage dependence of activation and inactivation can result in window currents, persistent currents that occur at voltages covered by the overlap. These sustained currents can contribute to enhanced excitability or, paradoxically, depolarization block.

Numerous factors have been implicated in modulating inactivation of voltage-gated sodium channels, including accessory subunits, toxins, genetic mutations, and post-translational modifications (Pei et al., 2018). The beta-4 subunit can induce an interesting form of inactivation (Bant & Raman, 2010). While classic inactivation induces a refractory state that is relieved following prolonged hyperpolarization of the membrane potential and recovery to the resting state, the beta-4 subunit can cause an open channel blocked state that initially resembles classic inactivation but that results in resurgent sodium currents during mild repolarizations. These resurgent currents, which can be enhanced by painful disease mutations (Jarecki, Piekarz, Jackson, & Cummins, 2010), result from relief of the open channel block during the downstroke of action potentials, increasing repetitive firing and cell excitability (Khaliq, Gouwens, & Raman, 2003; Raman, Sprunger, Meisler, & Bean, 1997).

In addition to IFM-mediated fast inactivation, voltage-gated sodium channels can enter a slow inactivation state in response to prolonged depolarizations (Cannon, 1996). Fast and slow inactivation are kinetically and functionally distinct. The time constant for entering or leaving the slow inactivated state is on the order of tens of seconds rather than milliseconds as for fast inactivation (Cummins & Sigworth, 1996). Removal of fast inactivation by enzyme treatment has been reported to have little effect on slow inactivation (Rudy, 1978). The voltage dependence of slow inactivation is different from that of fast inactivation (Cannon, 1996; Cummins & Sigworth, 1996).

Noncanonical Roles for Sodium Channels

In the context of drug development, it is important to recall the significant functions of sodium channels outside the nervous system. For example, sodium channels in the pancreas play an important role in the release of insulin (Q. Zhang et al., 2014). An interaction between sodium channels and glucose has also been identified that may be important in terms of the development of diabetes (C. Chen et al., 2018). Sodium channels have also been linked to cancer metastases. Some cancers express NaV1.5 splice variants; for example, a neonatal isoform of NaV1.5 (seven amino acid differences) is the predominant sodium channel (>80%) in human metastatic breast cancer (Yamaci et al., 2017) as well as neuroblastoma (Ou et al., 2005). NaV1.5 antagonists appear to have useful antimetastatic activity, although it is hard to envisage the therapeutic use of such cardiotoxic drugs in vivo (Dutta et al., 2018).

Multiple isoforms of sodium channels are present within astrocytes (Sontheimer, Black, Ransom, & Waxman, 1992; Sontheimer & Waxman, 1992); expression of these channels is highly dynamic, depending on multiple factors including developmental stage (Sontheimer, Ransom, Cornell-Bell, Black, & Waxman, 1991), and changing in a variety of pathological states. Expression of NaV1.5 sodium channels is strikingly upregulated in reactive (scarring) astrocytes in multiple sclerosis and stroke (Black, Newcombe, & Waxman, 2010). Sodium channels appear to contribute to scarring by astrocytes at least in part by triggering reverse Na+/Ca2+ exchange, which triggers calcium influx and resultant calcium waves (Pappalardo, Samad, Black, & Waxman, 2014). Sodium channels also contribute to the control of activation of microglia and macrophages, and sodium channel blockade can, for example, attenuate phagocytosis in these cells (Craner et al., 2005).

Sodium Channel Isoforms and Pain

Multiple sodium channel isoforms have been implicated in modulating nociception and pain sensations. Eight of the nine mammalian isoforms have been identified in peripheral sensory neurons (with NaV1.4 as the exception). While NaV1.7, NaV1.8, and NaV1.9 are preferentially expressed in nociceptive neurons, several of the other isoforms have been implicated as possible targets for regulating pain. Although the link to pain is stronger with some isoforms than others, voltage-gated sodium channels play surprisingly diverse roles in sensory neuron electrogenesis and are an important array of targets for potential analgesics.

NaV1.1 (SCN1A) and NaV1.2 (SCN2A)

NaV1.1 (SCN1A) and NaV1.2 (SCN2A), the first sodium channels to be cloned, are expressed predominantly in the central nervous system, although they are also found in peripheral sensory neurons. Some gain-of-function mutations in NaV1.1 have been linked to a rare familial form of migraine, while loss-of-function mutations have been linked to epilepsy (Dichgans et al., 2005; Escayg et al., 2000). The diminished activity of inhibitory GABAergic interneurons expressing loss-of-function mutant channels is considered to underpin the pathogenesis of generalized epilepsy with febrile seizures (GEFS) and Dravet syndrome. Interestingly, haplo-insufficient NaV1.1 mice provide a model of autism (S. Han et al., 2012). A claim that NaV1.1 is associated with mechanical pain (measured through licking and biting) is unconvincing (Osteen et al., 2016). The toxins used in this study are also well-characterized potassium channel antagonists, and doses used for in vivo studies of the supposed selective NaV1.1-specific blocker were so high that any behavioral perturbations were likely to reflect actions on other sodium or potassium channels (Escoubas, Diochot, Celerier, Nakajima, & Lazdunski, 2002). None of the human mutations associated with NaV1.1 gain or loss of function have any effects on pain, mechanical or otherwise (with the possible exception of migraine).

NaV1.2 has been linked to rare cases of epilepsy and pain (Liao et al., 2010) and a variety of other disorders (Sanders et al., 2018). There are pharmacological insights that suggest that NaV1.2 may play a role in ciguatoxin-evoked pain (Zimmermann et al., 2013), and studies suggested that specific antagonists of NaV1.2 may have some analgesic effects (Rapacz et al., 2018). In general, however, NaV1.1 and NaV1.2 do not appear to be major pain targets.

NaV1.3 (SCN3A)

Sodium channel NaV1.3 (SCN3A), although absent or detectable at only low levels in adult DRG neurons, is upregulated at the transcriptional level following injury to the peripheral axons of DRG neurons (Black et al., 1999; Waxman, Kocsis, & Black, 1994). This NaV1.3 upregulation appears to be triggered, at least in part, by loss of access to peripheral pools of nerve growth factor (NGF) (Black, Langworthy, Hinson, Dib-Hajj, & Waxman, 1997). From a functional point of view, NaV1.3 produces a substantial response to small ramp-like stimuli and reprimes (recovers from inactivation) in a relatively rapid manner (Cummins et al., 2001); thus, the increased expression of NaV1.3 would be expected to contribute to the increased rapidly repriming sodium current that emerges following axotomy in small-diameter DRG neurons (Cummins & Waxman, 1997).

The role of NaV1.3 in pain is still a matter of controversy. Accumulation of NaV1.3 channels have been observed within the distal axon tips in experimental neuromas in rats (Black et al., 1999) and in human neuromas (Black, Nikolajsen, Kroner, Jensen, & Waxman, 2008), which are known to act as sites of ectopic impulse generation (Devor, 2006). Ectopic firing of injured DRG neurons is suppressed by TTX (X. Liu, Zhou, Chung, & Chung, 2001), and low doses of TTX reduce pain behavior in this animal model (Lyu, Park, Chung, & Chung, 2000), consistent with a contribution of NaV1.3 and other TTX-sensitive channels to ectopic discharges that contribute to pain from neuromas. On the other hand, normal neuropathic pain behavior has been reported in NaV1.3 knockout mice (Nassar et al., 2006). More recent evidence, however, has demonstrated that virus-mediated small hairpin RNA (shRNA) knockdown of NaV1.3 in DRG neurons attenuates nerve injury–induced neuropathic pain (Samad et al., 2013) and pain in experimental diabetes in rats (A. M. Tan, Samad, Dib-Hajj, & Waxman, 2015).

NaV1.4 (SCN4A)

NaV1.4 (SCN4A) is responsible for the generation and propagation of action potentials that initiate muscle contraction. Channelopathies of skeletal muscle involving NaV1.4 mutations have been identified, such as hyper- and hypokalemic periodic paralysis, paramyotonia congenita, and congenital myasthenic syndrome (Jurkat-Rott, Holzherr, Fauler, & Lehmann-Horn, 2010). Although NaV1.4 expression seems to be restricted to muscle, there is a report of myalgic pain associated with a mutant isoform (Suokas et al., 2012). Interestingly, these authors linked this phenotype to aspects of fibromyalgia pain. One possibility is that altered Nav1.4 activity in muscle could indirectly impact sensory neuron properties through extracellular signaling pathways.

NaV1.5 (SCN5A)

Unlike the skeletal muscle channel NaV1.4, the cardiac channel NaV1.5 (SCN5A) has been detected in a number of neuronal subtypes, including sensory neurons. Altered levels of DRG expression of NaV1.5 have been reported in animal models of neuropathic pain (Wang et al., 2018). Several syndromes leading to sudden cardiac death (Brugada syndrome) have been linked not only to NaV1.5 but also to NaV1.8, the genomic locus of which contains regulatory elements defining NaV1.5 expression levels. SCN5A mutations were found in about 20% of patients with Brugada syndrome (Yamagata et al., 2017), while 17% of cases involved mutations in NaV1.8 (Hu et al., 2014). NaV1.5 has been mainly linked to cardiac disease, but a novel SCN5A mutation was found in a patient who died with sudden unexpected death in epilepsy (SUDEP) (Aurlien, Leren, Tauboll, & Gjerstad, 2009). In addition, there is an important role for NaV1.5 in the interstitial cells of Cajal and smooth muscle of the human intestine. Mutations in NaV1.5 have been linked to inflammatory bowel disease, and around 2% percent of patients with irritable bowel syndrome have loss-of-function mutations in NaV1.5 (Beyder et al., 2014).

Nav1.6 (SCN6A)

The important general role of NaV1.6 (SCN6A) at nodes of Ranvier is well established. NaV1.6 contributes up to 60% of the TTX-sensitive sodium current in large DRG and about 34% in small DRG neurons (L. Chen et al., 2018). Gain-of-function mutations of NaV1.6 have been linked to trigeminal neuralgia (Tanaka et al., 2016), and the selective silencing of NaV1.6 ameliorates neuropathic pain in mice (L. Chen et al., 2018). Nodes of Ranvier are more closely spaced than normal along the abortively regenerating axons within neuromas (L. Chen et al., 2018); it is well established that along axons with closely spaced nodes of Ranvier, and especially at sites of geometrical inhomogeneity, action potential reflection, or abnormal impulse reflection duplication of impulses, can occur (Waxman & Brill, 1978). Since NaV1.6 is the most common channel at nodes of Ranvier, it probably contributes to this process. NaV1.6 is also a major generator of resurgent currents in many neurons (Cummins, Dib-Hajj, Herzog, & Waxman, 2005; Raman et al., 1997). Knockdown of NaV1.6 or beta-4 subunits reduces TTX-sensitive resurgent currents in DRG sensory neurons and reduces mechanical allodynia associated with local inflammation of the DRG (Xie, Strong, & Zhang, 2015; Xie et al., 2016).

NaV1.7 (SCN9A)

NaV1.7 (SCN9A) was cloned as a peripheral nervous system–specific sodium channel PN1 (Toledo-Aral et al., 1997). NaV1.7 is preferentially expressed within DRG neurons, trigeminal ganglion neurons, and sympathetic ganglion neurons (S. D. Dib-Hajj, Yang, Black, & Waxman, 2013) and is also expressed at high levels in olfactory sensory neurons (Ahn et al., 2011; Weiss et al., 2011). Although the functional significance is not clear, the voltage dependence of activation and of fast inactivation of NaV1.7 are both substantially hyperpolarized in olfactory sensory neurons compared to DRG neurons (Ahn et al., 2011).

Electrophysiological data suggest an important role of NaV1.7 within the rodent central nervous system. Although data are not available in humans, NaV1.7 is known to be expressed in the hypothalamus of rodents (Black, Hoeijmakers, Faber, Merkies, & Waxman, 2013; Branco et al., 2016). There is, in addition, evidence for a role of NaV1.7 in pancreatic islet cells in at least some species (Q. Zhang et al., 2014).

There is a quite remarkable relationship between some human heritable pain conditions and mutations in NaV1.7 (S. D. Dib-Hajj et al., 2017; Emery, Luiz, & Wood, 2016). Some dominant gain-of-function NaV1.7 mutations cause primary erythromelalgia, characterized by elevated skin temperature and burning of the distal extremities, especially the feet (Drenth & Waxman, 2007; Y. Yang et al., 2004). Such mutant channels often show hyperpolarizing shifts in voltage dependence of activation (Cummins, Dib-Hajj, & Waxman, 2004; Cummins, Sheets, & Waxman, 2007).

Other dominant gain-of-function mutations that impair NaV1.7 rapid inactivation can cause a distinct syndrome of paroxysmal extreme pain disorder leading to episodic pain in the rectum, as well as ocular and mandibular areas (Fertleman et al., 2006). Mutations associated with paroxysmal extreme pain disorder can induce prominent resurgent currents in NaV1.7 that are likely to contribute to enhanced sensory neuron excitability (Jarecki et al., 2010; Theile, Jarecki, Piekarz, & Cummins, 2011). Much rarer recessive loss-of-function conditions result in pain-free individuals (Cox et al., 2006) with no ability to smell (anosmia) (Weiss et al., 2011).

Consistent with the idea that NaV1.7 does not play a major role in the central nervous system, individuals with primary erythromelalgia do not exhibit cognitive abnormalities or seizures (Drenth & Waxman, 2007; McDonnell et al., 2016), and individuals with loss-of-function of NaV1.7 similarly do not display cognitive abnormalities, except for their inability to sense pain and their anosmia. These observations have made NaV1.7 a major target for analgesic drug development. Nevertheless, it is intriguing that affected individuals within two families carrying gain-of-function mutations substituting the 856 residue within NaV1.7 display a clinical syndrome characterized by underdevelopment of the distal limbs (Hoeijmakers, Faber, Lauria, Merkies, & Waxman, 2012; Tanaka et al., 2017). One of these individuals presented with electrolyte abnormalities suggestive of the syndrome of inappropriate antidiuretic hormone (Black et al., 2013). Expression of NaV1.7 is known to be elevated within magnocellular neurosecretory neurons of the rat supraoptic nucleus in response to osmotic stress (Black et al., 2013). Moreover, several cases of severe hypothermia have been reported in patients with primary erythromelalgia and NaV1.7 gain-of-function mutations (Seneschal, Sole, Taieb, & Ferrer, 2009; Tham, Li, Effraim, & Waxman, 2017). These findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and underscore the need for monitoring of hypothalamic function as NaV1.7 blocking agents are studied in clinical trials.

Overlap syndromes, with symptoms midway between inherited erythromelalgia and paroxysmal extreme pain disorder, have occasionally been encountered. In a patient whose clinical profile included features of both primary erythromelalgia and paroxysmal extreme pain disorder, the mutant NaV1.7 channel exhibited biophysical changes associated with both inherited erythromelalgia (hyperpolarized activation) and paroxysmal extreme pain disorder (impaired fast inactivation) (Estacion et al., 2008). Another complex phenotype is associated with an NaV1.7 mutation (I234T) that massively hyperpolarizes channel activation as a result of an extremely large overlap (predicted window current) between activation and fast inactivation (Figure 3). This mutation massively depolarizes some DRG neurons, inactivating their sodium channels and silencing them, so that, in addition to episodic pain, patients carrying this mutation sustain painless injuries (Huang et al., 2018).

Sodium Channels and PainClick to view larger

Figure 3. NaV1.7 channels are associated with multiple pain phenotypes. (A) Representative fast-activating and fast-inactivating NaV1.7 currents recorded from a DRG neuron. (B) Comparison of NaV1.7 activation (open symbols) and inactivation (filled symbols) for different classes of mutations. Wild-type (WT) curves are shown in black. Erythromelalgia (IEM) mutations predominantly shift activation (red curves). Paroxysmal extreme pain disorder (PEPD) mutations predominantly impair inactivation (blue curves). Mutations such as I234T can lead to enhanced pain or pain insensitivity due to increased window currents at negative potentials (green curves).

Gain-of-function NaV1.7 mutations have also been found in a common disorder, small-fiber neuropathy. This disorder, in which small-diameter (C-fiber and A-∂-fiber) axons are involved, is characterized clinically by pain (usually felt first and most intensely in the distal extremities) and autonomic dysfunction. Faber et al. (Faber, Hoeijmakers, et al., 2012) reported that 8 patients of a cohort of 28 with biopsy-confirmed small-fiber neuropathy carried NaV1.7 mutations. These mutations tend to be amino acid substitutions within intracellular linkers and loops within the channel protein and thus would be expected to have more subtle physiological signatures than the gain-of-function mutations associated with primary erythromelalgia. Indeed, Faber et al. (Faber, Hoeijmakers, et al., 2012) showed that these mutations produce small impairments in fast inactivation, together with impairments of slow inactivation. At the cellular level, these mutations lower thresholds of DRG neurons, increase their frequency of firing, and produce spontaneous firing.

In mice lacking NaV1.7 in all sensory neurons as well as sympathetic neurons, there is an almost-complete loss of acute, inflammatory, and neuropathic pain, consistent with human studies (Gingras et al., 2014; Minett et al., 2012). It is thus puzzling that, to date, highly selective NaV1.7 antagonists have shown little or no analgesic activity (Deuis et al., 2017; Emery et al., 2016). Drug development programs are discussed below. An explanation for this anomaly comes from the observation that loss of NaV1.7 has a number of effects on transcription, leading to enhanced sensory neuron expression of the precursor of leu- and met-enkephalin, preproenkephalin (Minett et al., 2015). In addition, downstream signaling from opioid receptor G protein–coupled receptors (GPCRs) is potentiated in the absence of NaV1.7 but not NaV1.8 (Isensee et al., 2017). Thus, deleting NaV1.7 seems to enhance endogenous opioid signaling in the peripheral nervous system. Consistent with this, the application of the opioid antagonist naloxone to NaV1.7 null mice or to one human null volunteer dramatically diminished the analgesia associated with channel loss (Minett et al., 2015).

The activation of the opioid system seems to require complete channel loss. Thus, application of 500 nM TTX (more than 20 times the half maximal inhibitory concentration [IC50] for NaV1.7) for 6 hours can induce preproenkephalin mRNA in sensory neurons, but partial channel block is ineffective. Lowering intracellular sodium can also induce preproenkephalin expression (Minett et al., 2015). Evidence that inactive NaV1.7 antagonists can prove effective analgesics when administered with subclinical doses of opioids has been presented (Deuis et al., 2017). Nav1.7 also has unusual biophysical properties, identified in the hypothalamus, in terms of integrating small depolarizations over time to produce action potentials. This activity could potentially amplify nociceptive input into the central nervous system (Branco et al., 2016).

NaV1.8 (SCN10A)

The TTX-resistant NaV1.8 (SCN10A) sodium channel is expressed selectively in sensory ganglia, particularly in small-diameter unmyelinated DRG neurons (Akopian et al., 1996). Mapping the pattern of expression of NaV1.8-expressing neurons has shown that vagal afferents may be closely apposed to neuroendocrine cells and have terminals in the gastrointestinal mucosa (Gautron et al., 2011). This raises the interesting prospect of roles other than nociception for NaV1.8-expressing neurons. It is already known that cells expressing NaV1.8 play an important role in driving psoriatic mechanisms through interactions with dermal dendritic cells that release cytokines (Riol-Blanco et al., 2014).

The biophysical properties of NaV1.8 are unusual in that NaV1.8 is relatively resistant to inactivation by depolarization (Akopian et al., 1996); moreover, NaV1.8 recovers rapidly from inactivation (S. D. Dib-Hajj, Ishikawa, Cummins, & Waxman, 1997). Although NaV1.8 activates at more depolarized potentials than other isoforms, it produces nearly 80% of the inward current responsible for the depolarizing phase of the action potential in nociceptive neurons (Renganathan, Cummins, & Waxman, 2001). In addition, because it is more resistant to inactivation by depolarization, in depolarized neurons it supports high-frequency repetitive firing and thus may play an important protective role in damaged tissues. This slowly inactivating, rapidly repriming channel also contributes to unique resurgent currents that are enhanced by inflammatory mediators (Figure 4) and contribute to neuronal excitability (Z. Y. Tan et al., 2014). These TTX-resistant resurgent currents are much slower than TTX-sensitive resurgent currents but can contribute to increased action potential firing in sensory neurons.

Sodium Channels and PainClick to view larger

Figure 4. NaV1.8 channels produce slow TTX-R resurgent currents. (A) Representative NaV1.8-type resurgent currents. (B) Representative NaV1.6-type resurgent currents. (C) Inflammatory mediators (IMS) can increase both TTX-R and TTX-S resurgent current amplitudes. Modified with permission from Z. Y. Tan et al., 2014.

NaV1.8 global null mutant mice are viable, fertile, and apparently normal and have reduced sensitivity to noxious mechanical stimuli (tail pressure), noxious thermal stimuli (radiant heat), and noxious cold stimuli (Akopian et al., 1999; Zimmermann et al., 2007). Furthermore, NaV1.8 is important in NGF-induced thermal hyperalgesia, although neuropathic pain behavior is normal in these mice following one model of peripheral nerve injury (Kerr, Souslova, McMahon, & Wood, 2001). Transgenic mice in which NaV1.8-expressing neurons are ablated by the targeted expression of diphtheria toxin A are resistant to noxious cold and noxious mechanical stimuli, but show a normal hot plate response (Abrahamsen et al., 2008). Optogenetic silencing of NaV1.8-positive neurons confirmed the knockout data, reducing both inflammatory and neuropathic pain (Daou et al., 2016). Mice expressing gain-of-function NaV1.8 mutations have hyperexcitable A and C fibers but no spontaneous pain phenotype (Garrison, Weyer, Barabas, Beutler, & Stucky, 2014).

Genetic data confirmed the significance of NaV1.8 in human pain (Faber, Lauria, et al., 2012; C. Han, Huang, & Waxman, 2016). Some gain-of-function mutations of NaV1.8 cause small-fiber neuropathy (Faber, Lauria, et al., 2012; C. Han et al., 2016), while other gain-of-function mutations in NaV1.8 correlate with a syndrome with characteristics similar to erythromelalgia (Kist et al., 2016). In addition, SCN10A single-nucleotide polymorphisms (SNPs) influence mechanical pain thresholds. The Ala1073 Val nonsynonymous SNP shows faster inactivation, with a consequent increase in mechanical pain thresholds (Duan et al., 2016). Idiopathic painful neuropathy has also been linked to mutations in NaV1.8, some of which showed clear gain of function (Huang et al., 2013). Perhaps surprisingly, there are no reports of pain-free people associated with loss of NaV1.8 function. This may be due to the essential role of NaV1.5 in cardiac function and the regulatory interplay between SCN5A and SCN10A expression that makes NaV1.8 loss-of-function mutations lethal.

NaV1.8 has been linked to a number of pain states, particularly inflammatory pain. Many inflammatory mediators (e.g., prostaglandin E2 [PGE2]) potentiate NaV1.8 activity through phosphorylation of intracellular serine residues mediated by protein kinase A (PKA) and enhanced trafficking downstream of GPCR activation (Fitzgerald et al., 1999; C. Liu, Li, Su, & Bao, 2010). Yeast two-hybrid studies of NaV1.8 interactors have identified p11 as a key cofactor in membrane expression (Okuse et al., 2002). Visceral pain also appears to have a large NaV1.8-dependent component as both colitis and referred visceral pain are attenuated in the NaV1.8 null mutant (Laird, Souslova, Wood, & Cervero, 2002). In addition, a role for enhanced membrane expression of NaV1.8 in cancer-induced bone pain has been described (X. D. Liu et al., 2014). Lysophosphatidic receptor 1 is closely linked to NaV1.8, and both are upregulated in bone cancer. In this pain condition, protein kinase C (PKC) seems to be the key modulator of enhanced NaV1.8 function that contributes to bone cancer pain (Pan, Liu, Lin, & Zhang, 2016).

NaV1.9 (SCN11A)

NaV1.9 (SCN11A) is the most recent voltage-gated sodium channel to be identified (S. D. Dib-Hajj et al., 1998). This TTX-resistant sodium channel, initially called NaN, has a number of unique biophysical attributes. These include slow activation and even slower (almost nonexistent) inactivation (Figure 5) and a very broad overlap between the Boltzmann curves for activation and inactivation, centered on resting potential (Cummins et al., 1999). The NaV1.9 current initially eluded detection largely because it is subject to strong ultraslow inactivation, thus being almost undetectable at resting potential, but it can be clearly seen when neurons are hyperpolarized and held at potentials close -120 mV (Cummins et al., 1999). Guanosine triphosphate (GTP) (Baker, Chandra, Ding, Waxman, & Wood, 2003) and inflammatory mediators such as PGE2 (Rush & Waxman, 2004) increase the NaV1.9 current, probably at least in part via phosphorylation.

Sodium Channels and PainClick to view larger

Figure 5. NaV1.9 channels play an important role in pain. The top panel shows classic slowly inactivating NaV1.9 currents. The bottom NaV1.9 schematic illustrates the locations of pain-enhancing and pain-impairing NaV1.9 mutations.

NaV1.9 is preferentially expressed in small-diameter DRG neurons, trigeminal ganglion neurons, and myenteric neurons (S. Dib-Hajj, Black, Cummins, & Waxman, 2002; Fang et al., 2002, 2006; Rugiero et al., 2003). The channel appears to be expressed not only within cell bodies, but also within distal nerve terminals and at central terminals within the dorsal horn. In rodents, NaV1.9 can be detected within magnocellular neurosecretory cells within the hypothalamic supraoptic nucleus under some conditions (Black, Vasylyev, Dib-Hajj, & Waxman, 2014). As expected from the broad overlap between activation and inactivation, Nav1.9 has a depolarizing effect on resting membrane potential (Baker et al., 2003). Computer simulations indicated that, even at 50% of its normal density within DRG neuron cell bodies, NaV1.9 produced about 70% of its full depolarizing effect at normal density in DRG neuron cell bodies (Herzog et al., 2001).

Although the precise role of NaV1.9 in pain remains incompletely understood, its presence within nociceptors is incontrovertible, and molecular genetic studies have provided a strong link to pain in humans. Gain-of-function mutations of NaV1.9 have been described in a rare disorder called familial episodic pain, in which, beginning early in childhood, affected family members experience pain, focused largely in the lower extremities, that is exacerbated by fatigue and accompanied by sweating (X. Y. Zhang et al., 2013). The painful areas feel cold, and in some cases the pain is relieved by warmth and also by treatment with nonsteroidal anti-inflammatory drugs.

More recently, gain-of-function mutations of NaV1.9 have been described in a small percentage of patients with painful peripheral neuropathy (C. Han et al., 2015; Huang et al., 2014). Interestingly, in addition to sensory complaints of numbness, tingling, and pain in the distal extremities, some of these patients complain of symptoms that are usually attributed to autonomic dysfunction, such as a sensation of dry eyes, urinary problems, gastrointestinal abnormalities, palpitations, or orthostatic dizziness. Although the physiological basis for these clinical complaints is not fully understood, they may be explained by the presence of NaV1.9 channels within free nerve endings in the cornea, nodose ganglia, and visceral afferent neurons (Huang et al., 2014).

In a small number of patients, NaV1.9 mutations have been linked to a syndrome that includes insensitivity to pain, manifested by multiple painless orthopedic injuries, such as fractures, and absence of perception of pinprick as painful. In these cases, the NaV1.9 mutation produces a very large hyperpolarizing shift in voltage dependence of activation, which leads to a large sustained inward current, termed the window current. The resultant depolarization of resting potential is very large in some peripheral sensory neurons, inactivating the majority of TTX-sensitive (and even TTX-resistant) sodium channels within them so that they become hypoexcitable, providing an explanation for the lack of sensitivity to pain in patients carrying these mutations (Huang et al., 2017).

Therapeutic Horizons

Analgesic strategies focusing on sodium channels range from small-molecule blockers, through antibodies and antisense oligonucleotides, to gene therapy. At present, a number of sodium channel blockers are under investigation as analgesics, focusing mainly on NaV1.7, NaV1.8, and NaV1.9. Natural products, particularly toxins, have been identified as selective channel blockers, although these have not so far been followed up in terms of clinical development, often because of expense of manufacture or stability and delivery issues. Thus, a conotoxin, MrVIB, is a useful analgesic targeting NaV1.8 in rodent models of pain (Ekberg et al., 2006; Ji, 2018).

Several other small-molecule blockers of NaV1.8 have been shown to have analgesic activity in animal models. The orally available NaV1.8 channel blocker PF-01247324 inhibits human DRG TTX-resistant channels and shows at last 50-fold selectivity over other sodium channels. Neuronal excitability is diminished, and both inflammatory and neuropathic pain in rats is reduced on application of this compound (Payne et al., 2015). Ambroxol, available in the clinic for many years as a mucolytic compound, has some selectivity as a NaV1.8 blocker and has been shown to have analgesic effects in animal models (Gaida, Klinder, Arndt, & Weiser, 2005). A830657 is a potent analgesic when delivered systemically in animal models and, interestingly, is most potent when delivered intrathecally (McGaraughty et al., 2008). In 2018, Vertex announced the completion of a Phase 2 clinical trial with a further selective NaV1.8 antagonist. Although Nav1.8 and Nav1.9 are intuitively attractive for the development of isoform-specific inhibitors because they have much lower overall sequence conservation compared to the other isoforms, Nav1.9 has been more difficult to study in both native cells (due to relatively rapid rundown) and expression systems (due to poor expression in most systems).

NaV1.7 is a particularly interesting analgesic drug target because of the genetic data that validate it as a target in humans. The Pfizer drug PF-05089771, which has subtype-specific inhibitory action on NaV1.7, was studied in a double-blinded, placebo-controlled study of a cohort of five human subjects with primary erythromelalgia due to NaV1.7 gain-of-function mutations (Cao et al., 2016). Patient-specific induced pluripotent stem cells-derived sensory neurons were created from four of these human subjects. Three of these four cell lines showed hyperexcitability in response to warmth, and PF-05089771 attenuated the abnormal excitability and aberrant response to warmth in these cell lines. In each of these three patients, the NaV1.7 blocker attenuated heat-evoked pain in at least one of two trials, and in two of these patients it reduced pain in both of the trials (Cao et al., 2016).

Another sodium channel blocker with a substantial activity-dependent effect on NaV1.7, but with isoform specificity that has been questioned, was assessed by Convergence/Biogen in a study in 29 patients with trigeminal neuralgia (15 treated with the blocker; 14 treated with placebo). Although the primary endpoint (time to dropout) was not achieved, there was a statistically significant decrease of the number of paroxysms, which was reduced by 45%, and the average daily pain score, which was reduced by 50% (Zakrzewska et al., 2017). Monoclonal antibodies that show blocking activity were reported in 2016, but these results have not been replicated (D. Liu et al., 2016).

A centipede toxin that was claimed to block NaV1.7 and cause dramatic analgesia (S. Yang et al., 2013) has proved to be inactive. Other natural products have been reported to be excellent analgesics. For example, JingZhaotoxin-34 (JZT-34) is a selective blocker of NaV1.7 that is claimed to be more potent than morphine in the hot plate assay (Zeng et al., 2018). In terms of clinical efficacy, it is important to recognize that antagonists that may be useful in unusual gain-of-function pain conditions like erythermalgia or paroxysmal extreme pain disorder (PEPD) may not necessarily be useful in treating other pain syndromes. An experimental validation of this comes from studies of the potent tarantula toxin Pn3a. This peptide can completely reverse NaV1.7-dependent pain evoked by the NaV1.7 activator OD1, but is ineffective as an analgesic in formalin-evoked pain (Deuis et al., 2017). A substantial number of small -molecule NaV1.7 antagonists have been developed and assessed as analgesics.

An alternative strategy to the development of isoform-specific blockers is to target specific gating modes. Cannabidiol, which can preferentially target resurgent sodium currents (Patel, Barbosa, Brustovetsky, Brustovetsky, & Cummins, 2016), has shown some efficacy in treating seizures (Devinsky et al., 2018). Similarly, compounds that preferentially reduce persistent currents may be useful in blunting pain sensations without fully blocking sensory neuron activity. Development of peripherally restricted sodium channel blocker variants has also been pursued (McGowan, Hoyt, Li, Lyons, & Abbadie, 2009). Although cardiotoxicity could still be a concern, peripherally restricted blockers should have fewer central nervous system side effects, and compounds that target multiple peripheral isoforms could work in a larger array of pain conditions.

In parallel with the development of isoform-specific sodium channel blockers, there has been progress in the development of pharmacogenomic (genomically guided) use of existing sodium channel blockers for treatment of pain. For example, on the basis of atomic-level molecular modeling and thermodynamic analysis, which predict pharmacoresponsiveness of specific NaV1.7 variants (Y. Yang et al., 2012), a blinded clinical study was carried out, showing that, as predicted, carbamazepine reduced pain in human subjects carrying these mutations (Geha et al., 2016). Although the number of patients successfully treated on the basis of this approach is currently small, these studies suggest that the goal of genomically guided pharmacotherapy for patients with pain is not unrealistic.

Summary

There is extensive evidence that multiple voltage-gated sodium channel isoforms can play important roles in pain. NaV1.7, NaV1.8, and NaV1.9 are appealing targets for analgesics because of the prominent expression in nociceptive neurons. However, evidence suggests that NaV1.3 and NaV1.6 can also significantly modulate pain, at least in some conditions. NaV1.7 has substantial genetic validation from human studies and animal models. However, major efforts targeting NaV1.7 have met with limited success. The complex array of voltage-gated sodium channels in neurons and the importance of endogenous opioid system signaling in regulating pain suggest that a more comprehensive strategy is needed to achieve effective analgesia in multiple pain conditions.

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