Sodium channels in pain disorders: pathophysiology and prospects for treatment

Dib‐Hajj, Sulayman D.; Geha, Paul; Waxman, Stephen G.

doi:10.1097/j.pain.0000000000000854

Cited by 69 publications

(48 citation statements)

References 126 publications

(197 reference statements)

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“…Genetic evidence also supports investigative efforts to develop Nav1.7 blockers as a novel therapeutic strategy. These are undergoing clinical trials 2,91. Finally, advancement in electrophysiology, molecular modeling, thermodynamic analysis, and functional analyses profiling is improving our understanding of the molecular mechanisms underlying pain in EM 51.…”

Section: Resultsmentioning

confidence: 99%

Current pain management strategies for patients with erythromelalgia: a critical review

Tham¹,

Giles²

2018

JPR

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Erythromelalgia (EM) is a rare disorder characterized by erythematous, warm, painful extremities, which is often precipitated by cold conditions. The pathophysiology of EM is incompletely understood. Recent investigations have identified sodium channelopathy as a genetic cause for this pain condition, classified as primary inherited EM. Other subtypes are idiopathic EM and secondary EM. The management of pain in EM is challenging as no single therapy has been found to be effective. There is varying response to pharmacotherapy and significant variability within this clinical population, resulting in a stepwise trial and error approach. Consequently, EM is often associated with poorer health-related quality of life with higher morbidity. There is currently no consensus or guidelines on management of pain in EM. This is a review of the literature on management of pain using pharmacologic, procedural intervention and nonpharmacologic treatment in children and adults with EM.

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Section: Resultsmentioning

confidence: 99%

Current pain management strategies for patients with erythromelalgia: a critical review

Tham¹,

Giles²

2018

JPR

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“…Critical changes in ion channels, in particular sodium channels, arise after nerve injury, thought to produce abnormal peripheral transmission to the spinal cord and we have proof of concept since mutations in some of these peripheral sensors and channels cause human familial pain disorders [ 19 ]. The description of certain sodium channels, namely Nav 1.7 and 1.8, which are preferentially found in small fibers, lead to the possibility that their blockers could be novel analgesics with pain-selective actions, unlike present drugs such as lidocaine, which also blocks large fibers.…”

Section: Peripheral Events That Generate Neuropathic Painmentioning

confidence: 99%

Hopes for the Future of Pain Control

2017

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Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal’s equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain.

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“…Human Na V 1.7 (hNa V 1.7) has been identified as an important channel playing a crucial role in human pain signaling [ 8 ]. It is preferentially expressed in peripheral neurons, including peripheral somatic and visceral sensory neurons within the dorsal-root ganglia, sympathetic ganglion neurons, myenteric neurons and olfactory–sensory neurons [ 9 , 10 ]. In humans, gain-of-function mutations of hNa V 1.7 lead to severe neuropathic pain, such as inherited erythromelalgia (IEM) [ 11 , 12 , 13 ], paroxysmal extreme pain disorder (PEPD) [ 14 , 15 ] and idiopathic small-fiber neuropathy (SFN) [ 16 ], while loss-of-function mutations cause congenital insensitivity to pain (CIP) [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel

Zhang

Yang

Peng

et al. 2018

Toxins

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Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. Human voltage-gated sodium channel NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting spider toxin (NaSpTx) family 1, has shown negligible activity on mammalian voltage-gated sodium channels (VGSCs), including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G–N23S–D26H–L32W with >300-fold improved potency compared with wild-type HNTX-I on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel.

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Sodium channels in pain disorders: pathophysiology and prospects for treatment

Cited by 69 publications

References 126 publications

Current pain management strategies for patients with erythromelalgia: a critical review

Current pain management strategies for patients with erythromelalgia: a critical review

Hopes for the Future of Pain Control

Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel

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