Painful and painless channelopathies

doi:10.1016/S1474-4422(14)70024-9

The Lancet Neurology

Volume 13, Issue 6, June 2014, Pages 587-599

https://doi.org/10.1016/S1474-4422(14)70024-9 Get rights and content

Summary

The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Na_v1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Na_v1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Na_v1.8 (SCN10A) and Na_v1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development—eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development.

Introduction

Rapid growth is taking place in the discovery of rare genetic variants associated with mendelian disorders of pain perception. Progress has been made because of enhanced ascertainment of patients with pain disorders, greatly improved phenotyping, and new sequencing and bioinformatics technologies. In some individuals, gene mutations lead to insensitivity to pain, whereas in others, mutations lead to increased pain perception. Many variants reside in genes encoding ion channels, which play an important part in determining the excitability and function of nociceptors. Restricted expression of these molecules in sensory neurons, and their pivotal role in chronic and acute pain states, means that these genetic findings are now being translated into analgesic drug discovery programmes.

Chronic pain represents a substantial health burden, affecting one in five people in Europe; for 40% of these individuals, treatment is inadequate.¹ Common acquired chronic pain states are associated with altered expression and dysfunction of ion channels. Application of modern genomics to persistent pain states is challenging because of the complexity of phenotyping and the large cohort sizes needed; early findings suggest, however, that variants in ion channels modulate the risk, severity, and persistence of pain after injury. In this Review, we discuss recent advances in the understanding of the molecular basis of nociception, describe the clinical features and genetics of mendelian disorders of pain perception, and highlight the role of ion channels in acquired pain syndromes.

Section snippets

Ion-channel function in nociceptors

The term nociceptor was originally coined to describe sensory neurons that detect high-threshold stimuli causing—or with the potential to cause—tissue injury.² Such stimuli include extremes of temperature, mechanical force, or chemicals (eg, acid or prostaglandins).3, 4 The soma of nociceptors resides in dorsal root or trigeminal ganglia, and the neurons have unmyelinated or small-diameter myelinated axons. Nociceptors have a pseudo-unipolar morphology; a peripheral terminal innervates a target

Congenital insensitivity to pain

Hereditary sensory and autonomic neuropathies (HSANs) are a clinical group of inherited disorders in which sensory and autonomic neurons either fail to develop or degenerate.³⁶ They are classified according to the neuronal population implicated and the associated clinical features. Involvement of nociceptors results in insensitivity to noxious stimuli. For example, NGF is a key neurotrophic factor needed for target-derived survival of nociceptors.³⁷ Mutations in NGF³⁸ (which cause HSAN type V)

Inherited erythromelalgia

Erythromelalgia is a symptom complex of pain and erythema of the hands and feet.⁵⁰ The disorder usually starts in the feet but can affect the hands and, occasionally, the nose and ears. Pain is initially episodic, with attacks precipitated by warmth (such that most patients are unable to wear enclosed shoes), exercise, prolonged standing, and sometimes alcohol; the pain is relieved by cooling.51, 52 In some patients, pain becomes constant, with fluctuations. Pain is severe and disabling, and

Gene variants and risk of developing chronic acquired pain syndromes

Polymorphisms in the genes encoding ion channels might affect an individual's susceptibility to, and severity of, chronic pain after tissue inflammation or neural injury (table 2).81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 Testing this hypothesis has been challenging not only because detailed pain phenotyping is needed but also in view of the number of patients required to power such studies adequately. Chronic pain is not a homogeneous occurrence, many pathophysiological mechanisms can coexist

Treatments for pain that target ion channels

New analgesics effective for the treatment of chronic pain are needed urgently. Current agents that have activity directed against ion channels (eg, GABApentinoids, carbamazepine, and mexiletine) were not developed as analgesics but as antiepileptic or antiarrhythmic drugs. None are highly efficacious, and we cannot predict efficacy in individual patients.⁹⁸ Most agents have side-effects that can limit their usefulness in practice. Ion-channel genes are good candidates for novel analgesic

Conclusions and future directions

Understanding the genetic basis of rare heritable human pain disorders has improved our knowledge of pain pathophysiology and, perhaps unsurprisingly, highlighted the key functions of ion channels expressed in nociceptors. Perhaps what was unexpected is the primacy of the three voltage-gated sodium channels—Na_v1.7, Na_v1.8, and Na_v1.9—in acute pain sensing. Polymorphisms in mendelian pain genes might also establish the risk and severity of acquired pain states, such as painful diabetic

Search strategy and selection criteria

We searched PubMed between January, 1990, and Nov 1, 2013, for papers published in English, using combinations of terms including: “SCN9a”, “SCN10a”, “SCN11a”, “Na_v1.7”, “Na_v1.8”, “Na_v1.9”, “TRPa1”, “erythromelalgia”, “paroxysmal extreme pain disorder”, “small fibre neuropathy”, and “familial episodic pain disorder”. The final reference list was generated on the basis of relevance to the topics covered in this Review. Our primary sources stem from our own clinical and research practices, which

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Painful diabetic neuropathy (PDN) is a common chronic complication of diabetes that causes neuropathic pain and negatively affects the quality of life. The management of PDN is far from satisfactory. At present, interventions are primarily focused on symptomatic treatment. Ion channel disorders are a major cause of PDN, and a complete understanding of their roles and mechanisms may provide better options for the clinical treatment of PDN. Therefore, this review summarizes the important role of ion channels in PDN and the current drug development targeting these ion channels.
Overarching pathomechanisms in inherited peripheral neuropathies, spastic paraplegias, and cerebellar ataxias
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International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development. We highlight common cellular alterations that underlie this genetic landscape, including alteration of cytoskeleton, axonal transport, mitochondrial function, and DNA repair response. Finally, we discuss venues for future research using the long axonopathies of the PNS as a model to explore other neurogenetic disorders.
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Neuromodulatory treatments like spinal cord stimulation and dorsal root ganglion stimulation (DRGS) have emerged as effective treatments to relieve pain in painful polyneuropathy. Animal studies have demonstrated that neurostimulation can enhance nerve regeneration. This study aimed to investigate if DRGS may impact intraepidermal nerve fiber regeneration and sensory nerve function.
Nine patients with chronic, intractable painful polyneuropathy were recruited. Intraepidermal nerve fiber density (IENFD) quantification in 3 mm punch skin biopsy was performed 1 month before DRGS (placed at the level of the L5 and S1 dorsal root ganglion) and after 12- and 24-month follow-up. Quantitative sensory testing, nerve conduction studies, and a clinical scale score were also performed at the same time points.
In 7 of 9 patients, DRGS was successful (defined as a reduction of ≥ 50% in daytime and/or night-time pain intensity), allowing a definitive implantable pulse generator implantation. The median baseline IENFD among these 7 patients was 1.6 fibers/mm (first and third quartile: 1.2; 4.3) and increased to 2.6 fibers/mm (2.5; 2.9) and 1.9 fibers/mm (1.6; 2.4) at 1- and 2-years follow-up, respectively. These changes were not statistically significant (p = 1.000 and 0.375). Sensory nerve tests did not show substantial changes.
Although not significant, the results of this study showed that in most of the patients with implants, there was a slight increase of the IENFD at the 1- and 2-year follow-up. Larger-scale clinical trials are warranted to explore the possible role of DRGS in reversing the progressive neurodegeneration over time.
The Clinicaltrials.gov registration number for the study is NCT02435004; Swiss National Clinical Trials Portal: SNCTP000001376.
Advances and challenges in neuropathic pain: a narrative review and future directions
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Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.
Evaluating pain behaviours: Widely used mechanical and thermal methods in rodents
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Globally, over 300 million surgical procedures are performed annually, with pain being one of the most common post-operative side effects. During the onset of injury, acute pain plays a protective role in alerting the individual to remove noxious stimuli, while long-lasting chronic pain without any physiological reason is detrimental to the recovery process. Hence, it created an urgent need to better understand the pain mechanism and explore therapeutic targets. Despite the hardship in performing human pain studies due to ethical considerations, clinically relevant rodent pain models provide an excellent opportunity to perform pain studies. Several neurobehavioural tests are used to assess the drug efficacy in rodents to determine avoidance behaviour latency and threshold. This review article provides a methodological overview of mechanical (i.e. von Frey, Mechanical Conflict System) and thermal (i.e. Hargreaves Assay, Hot and Cold Plate, Temperature Place Preference) tests to assess pain in clinically relevant pain rodent models. We further discussed the current modifications of those tests along with their use in literature, the impact of confounding variables, advantages and disadvantages.
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Venom-derived Na_V1.7 channel blockers have promising prospects in pain management. The 34-residue tarantula peptide GpTx-1 is a potent Na_V1.7 channel blocker. Its powerful analog [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx-1 (GpTx-1-71) displayed excellent Na_V1.7 selectivity and analgesic properties in mice. The current study aimed to elucidate the anti-hyperalgesic activities of GpTx-1-71 in inflammatory pain and reveal the underlying mechanisms. Our results demonstrated that intrathecal and intraplantar injections of GpTx-1-71 dose-dependently attenuated CFA-induced inflammatory hypersensitivity in rats. Moreover, GpTx-1-71-induced anti-hyperalgesia was significantly reduced by opioid receptor antagonists and the enkephalin antibody and diminished in proenkephalin (Penk) gene knockout animals. Consistently, GpTx-1-71 treatment increased the enkephalin level in the spinal dorsal horn and promoted the Penk transcription and enkephalin release in primary dorsal root ganglion (DRG) neurons, wherein sodium played a crucial role in these processes. Mass spectrometry analysis revealed that GpTx-1-71 mainly promoted the secretion of Met-enkephalin but not Leu-enkephalin from DRG neurons. In addition, the combination of subtherapeutic Met-enkephalin and GpTx-1-71 produced synergistic anti-hyperalgesia in CFA-induced inflammatory hypersensitivity. These findings suggest that the endogenous enkephalin pathway is essential for GpTx-1-71-induced spinal and peripheral analgesia in inflammatory pain.
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ReviewPainful and painless channelopathies

Summary

Introduction

Section snippets

Ion-channel function in nociceptors

Congenital insensitivity to pain

Inherited erythromelalgia

Gene variants and risk of developing chronic acquired pain syndromes

Treatments for pain that target ion channels

Conclusions and future directions

Search strategy and selection criteria

Eur J Pain

Pain

Neuron

Neuron

Neuron

Neuron

Neuron

Neuron

Cell

Pain

Neuron

Neuron

Trends Neurosci

Cell

Eur J Pain

Pain

Pain

Exp Neurol

Pain

Neuron

Neuron

Am J Hum Genet

Cell

Neuron

Bioorg Med Chem

Qualitative difference of spinal reflex corresponding with qualitative difference of cutaneous stimulus

J Physiol

Nociceptors: the sensors of the pain pathway

J Clin Invest

Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond

Nat Rev Neurosci

Transient receptor potential channels: targeting pain at the source

Nat Rev Drug Discov

The capsaicin receptor: a heat-activated ion channel in the pain pathway

Nature

Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1

Nature

An ion channel essential for sensing chemical damage

J Neurosci

TRPA1 modulates mechanotransduction in cutaneous sensory neurons

J Neurosci

Regulation of TRP channels by phosphorylation

Neurosignals

Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons

Proc Natl Acad Sci USA

A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons

Nature

NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy

Proc Natl Acad Sci USA

Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel alpha subunit protein

J Physiol

Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn

Mol Pain

Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel

J Neurosci

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

Nature

Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons

Nat Commun

Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons

J Neurosci

Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons

J Neurophysiol

Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons

J Neurophysiol

Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior

Proc Natl Acad Sci USA

GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9

J Physiol

Review
Painful and painless channelopathies