The Role of Voltage-Gated Sodium Channels in Pain Signaling

Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.

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Rational development of analgesics for the treatment of chronic pain: dissecting the molecular details of the interaction between gating modifier peptide modulators and human voltage-gated sodium channels

10.14264/uql.2020.712 ◽

2020 ◽

Author(s):

Sassan Rahnama

Keyword(s):

Chronic Pain ◽

Sodium Channels ◽

Voltage Gated ◽

Rational Development ◽

Voltage Gated Sodium Channels ◽

Gating Modifier

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Sensory neuron voltage-gated sodium channels as analgesic drug targets

Current Opinion in Neurobiology ◽

10.1016/j.conb.2008.08.017 ◽

2008 ◽

Vol 18 (4) ◽

pp. 383-388 ◽

Cited By ~ 62

Author(s):

Aliakmal Momin ◽

John N Wood

Keyword(s):

Sodium Channels ◽

Sensory Neuron ◽

Drug Targets ◽

Analgesic Drug ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways

Toxins ◽

10.3390/toxins11110626 ◽

2019 ◽

Vol 11 (11) ◽

pp. 626 ◽

Cited By ~ 7

Author(s):

Yashad Dongol ◽

Fernanda Caldas Cardoso ◽

Richard J Lewis

Keyword(s):

Chronic Pain ◽

Sodium Channels ◽

Structural Features ◽

Voltage Gated ◽

Subtype Selectivity ◽

Voltage Gated Sodium Channels ◽

Neuronal Signalling ◽

Pain Pathways ◽

Nav Channels ◽

Chronic Pain Conditions

Voltage-gated sodium channels (NaVs) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit NaV channels have helped unravel the role of NaV channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate NaV channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of NaV subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key NaV subtypes make them the best lead molecules for the development of novel analgesics to treat chronic pain.

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The pattern of expression of the voltage-gated sodium channels Nav1.8 and Nav1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models

Pain ◽

10.1016/s0304-3959(01)00456-0 ◽

2002 ◽

Vol 96 (3) ◽

pp. 269-277 ◽

Cited By ~ 89

Author(s):

Isabelle Decosterd ◽

Ru-Rong Ji ◽

Salahadin Abdi ◽

Simon Tate ◽

Clifford J. Woolf

Keyword(s):

Neuropathic Pain ◽

Sodium Channels ◽

Sensory Neurons ◽

Primary Sensory Neurons ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Pain Models

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Trafficking Regulates the Subcellular Distribution of Voltage-Gated Sodium Channels in Primary Sensory Neurons

Molecular Pain ◽

10.1186/s12990-015-0065-7 ◽

2015 ◽

Vol 11 ◽

pp. s12990-015-0065 ◽

Cited By ~ 15

Author(s):

Lan Bao

Keyword(s):

Sodium Channels ◽

Sensory Neurons ◽

Subcellular Distribution ◽

Primary Sensory Neurons ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Neuropathic Pain Develops Normally in Mice Lacking both Nav1.7 and Nav1.8

Molecular Pain ◽

10.1186/1744-8069-1-24 ◽

2005 ◽

Vol 1 ◽

pp. 1744-8069-1-24 ◽

Cited By ~ 121

Author(s):

Mohammed A Nassar ◽

Alessandra Levato ◽

L Caroline Stirling ◽

John N Wood

Keyword(s):

Neuropathic Pain ◽

Sodium Channels ◽

Sensory Neurons ◽

Inflammatory Pain ◽

Pain Thresholds ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Pain Symptoms ◽

Α Subunits

Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

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Conserved Expression of Nav1.7 and Nav1.8 Contribute to the Spontaneous and Thermally Evoked Excitability in IL-6 and NGF-Sensitized Adult Dorsal Root Ganglion Neurons In Vitro

Bioengineering ◽

10.3390/bioengineering7020044 ◽

2020 ◽

Vol 7 (2) ◽

pp. 44

Author(s):

Rahul R. Atmaramani ◽

Bryan J. Black ◽

June Bryan de la Peña ◽

Zachary T. Campbell ◽

Joseph J. Pancrazio

Keyword(s):

Sodium Channels ◽

Sensory Neurons ◽

Inflammatory Pain ◽

Dorsal Root Ganglion Neurons ◽

Electrode Arrays ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Ganglion Neurons

Sensory neurons respond to noxious stimuli by relaying information from the periphery to the central nervous system via action potentials driven by voltage-gated sodium channels, specifically Nav1.7 and Nav1.8. These channels play a key role in the manifestation of inflammatory pain. The ability to screen compounds that modulate voltage-gated sodium channels using cell-based assays assumes that key channels present in vivo is maintained in vitro. Prior electrophysiological work in vitro utilized acutely dissociated tissues, however, maintaining this preparation for long periods is difficult. A potential alternative involves multi-electrode arrays which permit long-term measurements of neural spike activity and are well suited for assessing persistent sensitization consistent with chronic pain. Here, we demonstrate that the addition of two inflammatory mediators associated with chronic inflammatory pain, nerve growth factor (NGF) and interleukin-6 (IL-6), to adult DRG neurons increases their firing rates on multi-electrode arrays in vitro. Nav1.7 and Nav1.8 proteins are readily detected in cultured neurons and contribute to evoked activity. The blockade of both Nav1.7 and Nav1.8, has a profound impact on thermally evoked firing after treatment with IL-6 and NGF. This work underscores the utility of multi-electrode arrays for pharmacological studies of sensory neurons and may facilitate the discovery and mechanistic analyses of anti-nociceptive compounds.

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Neurotoxic peptides from the venom of the giant Australian stinging tree

Science Advances ◽

10.1126/sciadv.abb8828 ◽

2020 ◽

Vol 6 (38) ◽

pp. eabb8828

Author(s):

Edward K. Gilding ◽

Sina Jami ◽

Jennifer R. Deuis ◽

Mathilde R. Israel ◽

Peta J. Harvey ◽

...

Keyword(s):

Molecular Structure ◽

Sodium Channels ◽

Sensory Neurons ◽

Convergent Evolution ◽

3D Structure ◽

Cone Snail ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Sensory Effects ◽

Mammalian Skin

Stinging trees from Australasia produce remarkably persistent and painful stings upon contact of their stiff epidermal hairs, called trichomes, with mammalian skin. Dendrocnide-induced acute pain typically lasts for several hours, and intermittent painful flares can persist for days and weeks. Pharmacological activity has been attributed to small-molecule neurotransmitters and inflammatory mediators, but these compounds alone cannot explain the observed sensory effects. We show here that the venoms of Australian Dendrocnide species contain heretofore unknown pain-inducing peptides that potently activate mouse sensory neurons and delay inactivation of voltage-gated sodium channels. These neurotoxins localize specifically to the stinging hairs and are miniproteins of 4 kDa, whose 3D structure is stabilized in an inhibitory cystine knot motif, a characteristic shared with neurotoxins found in spider and cone snail venoms. Our results provide an intriguing example of inter-kingdom convergent evolution of animal and plant venoms with shared modes of delivery, molecular structure, and pharmacology.

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Sensory renal innervation: a kidney-specific firing activity due to a unique expression pattern of voltage-gated sodium channels?

AJP Renal Physiology ◽

10.1152/ajprenal.00011.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F491-F497 ◽

Cited By ~ 7

Author(s):

Wolfgang Freisinger ◽

Johannes Schatz ◽

Tilmann Ditting ◽

Angelika Lampert ◽

Sonja Heinlein ◽

...

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Sensory Neurons ◽

Firing Pattern ◽

Drg Neurons ◽

Action Potential Firing ◽

Tonic Firing ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Potential Firing

Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Navs). Dorsal root ganglion (DRG) neurons from rats (Th11-L2) were recorded by the current-clamp technique and distinguished as “tonic” or “phasic.” In voltage-clamp recordings, Navs were characterized by their tetrodotoxoxin (TTX) sensitivity, and their molecular identity was revealed by RT-PCR. The firing pattern of 66 DRG neurons (41 renal and 25 nonrenal) was investigated. Renal neurons exhibited more often a tonic firing pattern (56.1 vs. 12%). Tonic neurons showed a more positive threshold (−21.75 ± 1.43 vs.−29.33 ± 1.63 mV; P < 0.05), a higher overshoot (56.74 [53.6–60.96] vs. 46.79 mV [38.63–54.75]; P < 0.05) and longer action potential duration (4.61 [4.15–5.85] vs. 3.35 ms [2.12–5.67]; P < 0.05). These findings point to an increased presence of the TTX-resistant Navs 1.8 and 1.9. Furthermore, tonic neurons exhibited a relatively higher portion of TTX-resistant sodium currents. Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Navs.

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