Download Voltage-Gated Sodium Channels: Therapeutic Targets

PAIN MEDICINE
Volume 10 • Number 7 • 2009
Voltage-Gated Sodium Channels: Therapeutic Targets for Pain
pme_719
1260..1269
Sulayman D. Dib-Hajj, PhD, Joel A. Black, PhD, and Stephen G. Waxman, MD, PhD
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine,
New Haven, Connecticut, and Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System,
West Haven, Connecticut, USA
ABSTRACT
Objective. To provide an overview of the role of voltage-gated sodium channels in pathophysiology
of acquired and inherited pain states, and of recent developments that validate these channels as
therapeutic targets for treating chronic pain.
Background. Neuropathic and inflammatory pain conditions are major medical needs worldwide
with only partial or low efficacy treatment options currently available. An important role of
voltage-gated sodium channels in many different pain states has been established in animal models
and, empirically, in humans, where sodium channel blockers partially ameliorate pain. Animal
studies have causally linked changes in sodium channel expression and modulation that alter channel
gating properties or current density in nociceptor neurons to different pain states. Biophysical and
pharmacological studies have identified the sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and
Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently,
gain-of-function mutations in SCN9A, the gene which encodes Nav1.7, have been linked to two
human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder,
while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain.
Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects
of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence
of Nav1.8, which suggests a similar physiological interaction of these two channels in humans
carrying the Nav1.7 pain mutation.
Conclusions. These studies suggest that isoform-specific blockers of these channels or targeting of
their modulators may provide novel approaches to treatment of pain.
Key Words. Chronic Pain; Diabetic Neuropathy; Inflammation; Pain Disorder; Persistent Pain
Introduction
A
lthough pain is a complex perception, it often
has a peripheral origin which depends on
electrical activity within sensory neurons that
innervate the body surface and viscera. Within
these neurons, voltage-gated sodium channels
subserve the generation and conduction of action
potentials. This pivotal role of sodium channels in
Reprint requests to: Stephen G. Waxman, MD, PhD,
Department of Neurology LCI 707, Yale School of Medicine, 333 Cedar Street, PO Box 208018, New Haven, CT
06520-8018, USA. Tel: 203-785-5947; Fax: 203-785-7826;
E-mail: [email protected].
The authors have no relevant financial disclosures to
report.
electrogenesis has made them attractive targets for
pharmacotherapeutic approaches aimed at attenuating neuronal firing that result in pain. In this
article, we will review current knowledge of neuronal sodium channels as molecular targets, with
a major focus on the isoforms preferentially
expressed within dorsal root ganglion neurons,
which constitute the first-order cells along pain
signaling pathways.
Sodium channels are closed and inactive at rest
but undergo structural changes in response to
membrane depolarization, leading to cycling of
the channel through activated (open), inactive, and
repriming states [1]. Transient channel opening
allows a flow of sodium ions down their concentration gradient, thus generating an inward
© American Academy of Pain Medicine 1526-2375/09/$15.00/1260 1260–1269
doi:10.1111/j.1526-4637.2009.00719.x
Voltage-Gated Sodium Channels
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Figure 1 Schematic of the pore-forming a-subunit of voltage-gated sodium channel. The pore-forming subunit of sodium
channels is a long polypeptide with 24 transmembrane segments that are organized into four homologous domains (DI–DIV).
The N- and C-termini of the channel, and loops 1–3 (L1–L3) which joins the four domains are cytosolic and have been shown
to house sequence motifs for channel partner binding and for phosphorylation of the channel. The binding of different classes
of cytosolic proteins and phosphorylation of the channels have been shown to regulate channel trafficking and polarized
distribution within neuronal compartments, and/or biophysical properties of the channel. The S4 transmembrane segment in
each of the domains is a voltage sensor, and the gray sphere in L3 designate the tetrapeptide isoleucine-phenylalaninemethionine-threonine (IFMT), which acts as the fast-inactivating particle of the channel. The extracellular linkers may be sites
of N-glycosylation of channels.
transmembrane current that depolarizes neurons,
bringing them closer to the threshold for action
potential generation. Most channels rapidly inactivate, within milliseconds of opening, and then
undergo conformational changes to recover from
inactivation. Sodium channels are heteromultimers of a large a-subunit and smaller auxiliary
b-subunits [2]. The a-subunit is necessary and sufficient to produce a functional channel, while
b-subunits and other cytosolic channel partners
modulate biophysical properties of the channels
and regulate trafficking and anchoring of the
channels at the cell membrane. There are nine
different sodium channel isoforms (Nav1.1–
Nav1.9), all sharing a common overall structural
motif (Figure 1) but with differing amino acid
sequences, which cycle through these states
with different kinetics and voltage-dependent
properties [3].
Sodium Channels in Dorsal Root
Ganglion Neurons
Most types of neurons express multiple sodium
channel isoforms, with the complement of channel
subtypes influencing the firing properties of these
neurons. Dorsal root ganglion neurons from adult
rodents, for example, can express up to five sodium
Nav1.6–Nav1.9
channel
subtypes,
Nav1.1,
(Figure 2A). Nav1.1, Nav1.6, and Nav1.7 are sensitive to block by nanomolar concentrations of tetrodotoxin (TTX-S), while Nav1.8 and Nav1.9 are
resistant to the toxin block (TTX-R), requiring
micromolar concentrations of TTX for block [3].
Importantly, Nav1.7, Nav1.8, and Nav1.9 are preferentially expressed in peripheral neurons (all
three channels in dorsal root ganglion, and Nav1.7
in sympathetic neurons), presenting the possibility
of targeting sodium channels that do not have any
roles in the central nervous system (CNS) or heart.
The voltage dependence of activation and inactivation and the kinetics of Nav1.8 and Nav1.9 channels can be readily distinguished even in the
presence of other TTX-S sodium channels as the
latter can be completely blocked with nanomolar
concentrations of TTX (Figure 2B). In this article,
we review recent evidence showing that Nav1.3,
Nav1.7, Nav1.8, and Nav1.9 play especially important roles in pain.
Sodium Channels in Pain States Following Injury
or Inflammation
Several rodent models of nerve injury are commonly used in studies of neuropathic pain: sciatic
nerve transection which entails tight ligation and
severing of the sciatic nerve at the mid-thigh level,
spinal nerve ligation (SNL) which is produced by
tight ligature of the spinal nerve originating from
an individual dorsal root ganglion [4], spared nerve
injury in which the tibial and common peroneal
branches of the sciatic nerve are cut while sparing
the third (sural) branch [5], and chronic constriction
injury of the sciatic nerve which involves loose
ligatures around the sciatic nerve [6]. These
models have gained wide acceptance as pain
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Dib-Hajj et al.
Figure 2 Multiple sodium channels and currents in adult dorsal root ganglion neurons. Sodium channel a-subunit mRNAs
(left panels) and protein (right panels) visualized by subtype-specific riboprobes and antibodies, respectively. Transcripts and
protein for five different sodium channels (Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) are present at moderate-to-high levels
in dorsal root ganglion neurons. Nav1.2 and Nav1.3 are not detectable in adult dorsal root ganglion neurons. Scale bar,
50 mm. Voltage-gated sodium currents recorded by whole-cell patch-clamp in adult dorsal root ganglion neurons (right
panels). (A) Only fast, tetrodotoxin (TTX)-sensitive sodium current (presumably composed of Nav1.1, Nav1.6, and Nav1.7) is
observed in a muscle afferent dorsal root ganglion neuron. (A′) Activation (filled symbols) and steady-state inactivation (open
symbols) exhibit little overlap. (B) A small dorsal root ganglion neuron displays only slow, TTX-resistant sodium current
(Nav1.8). (B′) Activation (filled symbols) and steady-state inactivation (open symbols) curves are depolarized compared with
fast, TTX-sensitive current, and show significant overlap representing a range of voltages where the channel is predicted to
be open and conducting a current (window current). (C) Persistent, TTX-resistant sodium current (Nav1.9) recorded from a
small dorsal root ganglion neuron from Nav1.8-null mouse. (C′) Activation (open symbols) and steady-state inactivation (filled
symbols) show significant overlap (window currents). (Modified and reproduced with permission from [13,38,83–85].)
models because they are highly reproducible,
permit application of exogenous factors such as
neurotrophic factors or transformed cells that can
secrete desired factors, and are amenable to assessment of behavioral pain responses.
Nerve injury induces dynamic regulation of
sodium channel expression in dorsal root ganglion
neurons with gene transcription for some channels
that are “turned off” and others that are “turned
on” [7,8]. Nav1.3 channel expression which can be
detected at very low levels in adult rat dorsal root
ganglion neurons is upregulated in these neurons
[9–11]. However, the expression of Nav1.8 and
Nav1.9 is significantly attenuated in injured
Voltage-Gated Sodium Channels
neurons [11–14]. In contrast, levels of Nav1.1,
Nav1.6, and Nav1.7 are reduced but to a lesser
extent in dorsal root ganglion neurons following
injury [15,16]. The injury-mediated loss of mRNA
and protein for Nav1.8 and Nav1.9 in axotomized
dorsal root ganglion neurons are paralleled by
attenuation of their TTX-R currents in these
neurons [17–20]. Injury-induced upregulation of
Nav1.3 is accompanied by changes to the TTX-S
current which include an acceleration of repriming, an enhanced response to small slow depolarizations (ramp stimuli) [21], and larger persistent
current [22], which would be expected to contribute to hyperexcitability in injured dorsal root ganglion neurons.
Experimental rhizotomy, which involves transaction of central roots leading to spinal cord, does
not alter levels of Nav1.8 and Nav1.9, similar to
the absence of an effect on Nav1.3 levels [13].
However, a decrease in the level of expression of
Nav1.8 and Nav1.9 within injured dorsal root ganglion neurons has also been reported in human
patients suffering from brachial plexus injuries
that avulsed their central axons from the spinal
cord [23]. The difference between animal and
human findings remains poorly understood.
Chronic constriction injury, on the other hand,
is a mixed lesion in which transection of axons
is precipitated by inflammation, and in which
injured and intact fibers comingle along a significant part of the nerve [6]. Sodium channel expression following chronic constriction injury is
altered in a pattern similar to that following sciatic
nerve transection [24]. Chronic constriction
injury-induced changes in sodium channel expression in dorsal root ganglion neurons [24], and in
dorsal horn neurons [25] may contribute to pain
behavior in rats.
Neuromas which form at the site of nerve ligation can cause ectopic impulse generation and
spontaneous firing [26]. Elevated levels of the
Nav1.3 channel have been demonstrated within
distal axon tips in experimental neuromas in rats,
with only background levels of immunofluorescence at distances greater than 500–1,000 mm
proximal to this region [10]. Human neuromas
have been shown to display accumulation of
Nav1.7 and Nav1.8 [23,27,28]. Painful, but not
nonpainful, neuromas of the lingual nerve have
been shown to accumulate Nav1.7 [29]. Additionally, Black et al. [28] have also reported the accumulation of phosphorylated p38 and ERK1/2
mitogen-activated protein kinases (MAPK) within
axons in painful human neuromas. Biochemical
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and electrophysiological studies have shown that
p38 and ERK1/2 MAPK enhance the activity of
Nav1.8 [30] and Nav1.7 [31]. Thus, the entire suite
of molecules that accumulate within neuromas
may be as important as any single molecule in
producing ectopic firing.
Compression injuries to nerve roots or to dorsal
root ganglion underlie radicular pain. Neurons in
an animal model, chronic compression injury of
dorsal root ganglion, become spontaneously active
[32] and display an enhanced response to inflammatory mediators [33,34]. Molecular analysis has
shown that chronic compression injury of dorsal
root ganglion leads to dynamic regulation of
sodium channels but, unlike SNL or axotomy,
does not lead to an increase in Nav1.3 expression
or a decrease in Nav1.8 channel levels [35].
However, chronic compression injury of dorsal
root ganglion causes a shift in voltage dependence
of activation of TTX-S channels in a hyperpolarizing direction and an increase in the peak amplitude of the slow-inactivating TTX-R current, and
a decrease in voltage-gated potassium current
recordings from identified cutaneous afferents
[36]. These changes can contribute to compressed
dorsal root ganglion neuron hyperexcitability
resulting in radicular pain.
Inflammatory pain, similar to neuropathic pain,
is characterized by spontaneous activity of nociceptors, lowered threshold for action potential,
and stronger stimulus-evoked response. Sodium
channel blockers can attenuate inflammatory pain
(for a recent review, [37]). Animal studies have
demonstrated dynamic expression of sodium channels within nociceptors following inflammation of
skin and muscle [38] or viscera [39]. Knockout or
knockdown of specific sodium channels have identified Nav1.7, Nav1.8, and Nav1.9 as contributors
to inflammation-induced pain [40–48]. These
results demonstrate an important role of these
channels in inflammatory pain conditions.
Sodium Channels in Painful Diabetic Neuropathy
Streptozotocin-induced diabetic neuropathy
results in tactile allodynia several weeks following
onset of hyperglycemia, and manifests dysregulated sodium channel expression [49,50]. Hong
et al. [50] reported changes in the TTX-S and
TTX-R sodium currents in diabetic dorsal root
ganglion neurons which parallel changes of
sodium channel mRNA and protein levels in these
cells, and which would be expected to lower the
action potential threshold. Whole-cell patch-
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clamp recordings showed an increase in the
TTX-S peak current density and the amplitude of
the ramp current, consistent with upregulation of
Nav1.3, Nav1.6, and Nav1.7 channels which has
been shown to produce robust ramp currents
[21,51,52]. While a reduction in transcript and
protein levels of Nav1.8 were reported in diabetic
dorsal root ganglion neurons [49,50], whole-cell
patch-clamp studies show an increase in the slowly
inactivating TTX-R current and a hyperpolarized
shift of activation and steady-state inactivation,
consistent with the elevated levels of serine/
threonine phosphorylation of Nav1.8 in dorsal
root ganglion neurons from diabetic rats [50].
Irrespective of the underlying molecular mechanism, these changes of the sodium current are
predicted to enhance excitability of dorsal root
ganglion neurons from diabetic rats leading to the
neuropathy that is associated with this disorder.
Mutations of Sodium Channels in Human
Pain Disorders
The recent discovery of a genetic link in inherited
pain syndromes has advanced our understanding
of the contribution of sodium channels to pain in
humans. Gain-of-function mutations in SCN9A,
the gene which encodes sodium channel Nav1.7,
have been identified in patients with two severe
pain syndromes, inherited erythromelalgia [53,54]
and paroxysmal extreme pain disorder [55]. Lossof-function mutations of SCN9A have been identified in patients with congenital insensitivity to
pain which is accompanied by reported deficits in
smell [56,57].
Inherited Erythromelalgia
Mutations in SCN9A which underlie inherited
erythromelalgia were the first mutations in a
peripheral sodium channel to be linked to a painful
human pain disorder [58]. Inherited erythromelalgia is characterized by bilateral severe pain in the
extremities which is accompanied by cutaneous
vasodilation leading to skin reddening and
elevated temperature, but without global deficits
in temperature regulation or orthostatic pressure
[59,60]. Early-onset inherited erythromelalgia
(also known as erythermalgia) is an autosomal
dominant disorder which has been linked to missense mutations in Nav1.7 [58,61–67]. Electrophysiological recordings have shown that these
mutations lower the threshold for channel activation, and most enhance the ramp currents and
Dib-Hajj et al.
slow the rate of deactivation [61–63,68–72].
Expression of three mutant channels (Nav1.7/
F1449V, Nav1.7/L858H, and Nav1.7/A863P)
within dorsal root ganglion neurons lowers the
current threshold for action potential generation,
and increases the number of action potentials in
response to graded stimuli, both hallmarks of
hyperexcitable neurons (Figure 3 and [61,63,73]).
The expression of Nav1.7/L858H and Nav1.7/
A863P mutant channels in dorsal root ganglion
neurons caused a depolarization of the resting
membrane potential (RMP) [63,73]. The impact
of depolarization of RMP on the firing behavior of
neurons depends upon the complement of the
channels that are present in these neurons. Thus, a
depolarized RMP of dorsal root ganglion neurons
is closer to the activation threshold voltage of the
TTX-R channel Nav1.8 [74,75]. In contrast, depolarization of the RMP in neurons which do not
express Nav1.8 channels is predicted to cause inactivation of the TTX-S channels, which have
hyperpolarized voltage dependence of inactivation
compared with Nav1.8, and render these neurons
hypoexcitable [76]. This hypothesis was tested
experimentally by expressing the L858H mutant
Nav1.7 channels in dorsal root ganglion neurons
that carry Nav1.8 and in superior cervical ganglion
neurons which do not express Nav1.8, and studying the firing properties of these neurons [73]. The
expression of L858H mutant Nav1.7 in dorsal root
ganglion neurons rendered these neurons hyperexcitable, whereas its expression in superior
cervical ganglion neurons made these neurons
hypoexcitable [73]. The co-expression of Nav1.8
with Nav1.7/L858H in superior cervical ganglion
neurons restored near-normal excitability to these
neurons [73], demonstrating a physiological interaction of Nav1.7 and Nav1.8 in regulating firing
properties of neurons. However, these studies
showed that excitability of dorsal root ganglion
neurons expressing mutant Nav1.7 channels can
not be explained by a depolarized RMP alone [63],
suggesting that other changes in the properties of
mutant Nav1.7 channels also contribute to dorsal
root ganglion neuron hyperexcitability.
Paroxysmal Extreme Pain Disorder
Paroxysmal extreme pain disorder, previously
known as familial rectal pain [77,78], was the
second human pain disorder to be linked to a different set of mutations in Nav1.7 [55]. Paroxysmal
extreme pain disorder is characterized by severe
pain and flushing in the lower body in infants
Voltage-Gated Sodium Channels
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Figure 3 Inherited erythromelalgia Nav1.7/A863P mutation decreases action potential threshold and increases frequency of
firing in small, current-clamped dorsal root ganglion neurons. (A) Responses of a current-clamped dorsal root ganglion
neuron transfected with wild type (WT) Nav1.7 DNA to a series of subthreshold and suprathreshold depolarizing current
steps. Starting at a subthreshold stimulus intensity, the current amplitude was increased in 5 pA increments to an intensity
well beyond threshold. Resting membrane potential (RMP) for this cell was -55 mV and threshold was 310 pA. A dorsal root
ganglion neuron expressing WT channels responds to a 1-second depolarizing current step that is one, two, and three times
the current threshold for action potential generation by the firing of up to two spikes (at 3¥ threshold). (B) The same threshold
protocol applied to a dorsal root ganglion neuron transfected with the A863P mutant DNA elicits action potential with a
smaller current injection. RMP for this cell was -45 mV and threshold was 95 pA. Arrows with numbers indicate the current
step amplitude used to elicit the labeled response. A dorsal root ganglion neuron expressing A863P mutant channels
responds to a 1-second depolarizing current step that is one, two, and three times the current threshold for action potential
generation by the firing of up to 11 spikes (at 3¥ threshold). (Modified and reproduced with permission from [63].)
during bowel movement or probing of perianal
areas, which evolves with age to include ocular and
mandibular pain distributions [78,79]. Several
mutations have been shown to impair fast inactivation with no effect on channel activation [55,79–
81]. The mutant Nav1.7 channels allow more
sodium current to flow through and are predicted
to increase dorsal root ganglion neuron hyperexcitability. In fact, current-clamp recordings of
dorsal root ganglion neurons that express paroxysmal extreme pain disorder mutant Nav1.7 channels have demonstrated neuronal hyperexcitability
[79,80]. A1632E is considered a hybrid Nav1.7
mutation because it impairs inactivation as with
other paroxysmal extreme pain disorder mutations
and hyperpolarizes activation as with inherited
erythromelalgia mutations, and has been shown to
have a mixed clinical phenotype with features of
both disorders [79]. Patients with paroxysmal
extreme pain disorder tend to respond favorably to
treatment with carbamazepine [55,79,80], unlike
patients with inherited erythromelalgia who
usually do not benefit from pharmacotherapy
[59,60].
Nav1.7-Related Congenital Insensitivity to Pain
Loss-of-function mutations in SCN9A, which are
inherited as autosomal recessive traits, have been
linked to an inability to experience pain, a disorder
that has been called Nav1.7-related congenital
insensitivity to pain [56,57,82]. These patients
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have been reported to walk on hot surfaces and
tolerate puncture wounds and bone fractures, and
self-mutilate (biting lips and tongue without
feeling pain), but without other somatosensory
deficits including sensation of warmth or touch
[56]. While Nav1.7 is expressed within sympathetic ganglion neurons, these patients do not
exhibit apparent global sympathetic dysfunction.
All but one of the mutations causing Nav1.7related congenital insensitivity to pain are nonsense mutations which truncates the channel
protein, and one mutation that is predicted to
interfere with splicing so that mature mRNAs are
not produced [56,57,82]. The parents of affected
individuals are asymptomatic suggesting that
SCN9A does not cause haploinsufficiency. The
mutant channel with truncations of varying parts
of the protein produces no current when expressed
in the mammalian cell line HEK 293 or interferes
with other sodium channels that may be present
within the same neuron, suggesting a molecular
pathophysiological cause for the phenotype
[56,82]. Clinical observations of these patients
extend the findings of studies on Nav1.7-null mice
[41], in which nociceptive pain signaling and an
inflammatory pain response are attenuated, and
document the importance of Nav1.7 in pain states.
Prospects for New Pain Therapeutics
As illustrated above, there is now abundant evidence not only for a role of voltage-gated sodium
channels in pain but also pointing toward specific
sodium channel isoforms as major contributors to
chronic pain. Thus far, relatively nonspecific
sodium channel blockers, e.g., lidocaine and carbamazepine, have shown a significant degree of
efficacy in terms of treatment of chronic pain. The
partial nature of the pain relief afforded by these
existing medications underscores, however, the
need for newer and better pain therapeutics. In
this regard, the identification of specific sodium
channel isoforms—some of which are expressed
preferentially or solely within primary sensory
neurons—opens up the possibility of targeted
therapies aimed at ameliorating hyperexcitability
in pain signaling neurons without CNS or cardiovascular side effects. Moreover, the recent demonstration of painful disorders and loss of ability to
experience pain in humans, produced by gain-offunction or loss-of-function of a particular sodium
channel isoform, Nav1.7, suggests that translational efforts, aimed at moving new pain medications to the clinic, are not unrealistic. Whether it
Dib-Hajj et al.
will be possible to develop new molecules with this
degree of specificity and whether these agents will
in fact provide more effective clinical therapies for
pain remain to be determined. Given the rapid
pace of papers over the past few years, it is not
unlikely that answers to these questions will soon
begin to emerge.
Acknowledgments
We thank the members of our group for valuable discussions and technical assistance. This work is supported in
part by grants from the Rehabilitation Research and
Development Service and Medical Research Service,
Department of Veterans Affairs, the National Multiple
Sclerosis Society, and the Erythromelalgia Foundation.
The Center for Neuroscience and Regeneration Research
is a collaboration of the Paralyzed Veterans of America and
the United Spinal Association with Yale University.
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