PAK1 inhibition with Romidepsin attenuates H-reflex hyperexcitability after spinal cord injury.

Hyperreflexia associated with spasticity is a prevalent neurological condition characterized by excessive and exaggerated reflex responses to stimuli. Hyperreflexia can be caused by several diseases including multiple sclerosis, stroke and spinal cord injury (SCI). Although we have previously identified the contribution of the RAC1-PAK1 pathway underlying spinal hyperreflexia with SCI-induced spasticity, a feasible druggable target has not been validated.

Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability.

Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons.

High-throughput combined voltage-clamp/current-clamp analysis of freshly isolated neurons.

The patch-clamp technique is the gold-standard methodology for analysis of excitable cells. However, throughput of manual patch-clamp is slow, and high-throughput robotic patch-clamp, while helpful for applications like drug screening, has been primarily used to study channels and receptors expressed in heterologous systems. We introduce an approach for automated high-throughput patch-clamping that enhances analysis of excitable cells at the channel and cellular levels.

Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons.

Fibroblast growth factor homologous factors (FHFs) are cytosolic members of the superfamily of the FGF proteins. Four members of this subfamily (FHF1-4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders.

Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability.

Background And Purpose: Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor of ∆ -tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10 μM) blocks voltage-gated sodium (Na ) currents in CNS neurons, although the underlying mechanism is not well understood. Genetic and functional studies have validated Na 1.

Lacosamide Inhibition of Na1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore.

Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide's effect on Na1.

Contributions of Na1.8 and Na1.9 to excitability in human induced pluripotent stem-cell derived somatosensory neurons.

The inhibition of voltage-gated sodium (Na) channels in somatosensory neurons presents a promising novel modality for the treatment of pain. However, the precise contribution of these channels to neuronal excitability, the cellular correlate of pain, is unknown; previous studies using genetic knockout models or pharmacologic block of Na channels have identified general roles for distinct sodium channel isoforms, but have never quantified their exact contributions to these processes. To address this deficit, we have utilized dynamic clamp electrophysiology to precisely tune in varying levels of Na1.

variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.

There is a pressing need for understanding of factors that confer resilience to pain. Gain-of-function mutations in sodium channel Nav1.7 produce hyperexcitability of dorsal root ganglion neurons underlying inherited erythromelalgia, a human genetic model of neuropathic pain.

Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype.

Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN.

Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy.

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy.

A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane.

Genetic and functional studies have confirmed an important role for the voltage-gated sodium channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.

Dexpramipexole blocks Nav1.8 sodium channels and provides analgesia in multiple nociceptive and neuropathic pain models.

Selective targeting of sodium channel subtypes Nav1.7, Nav1.8, and Nav1.

A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy.

Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in α-subunits of voltage-gated sodium channels (Nas) in patients with painful diabetic peripheral neuropathy.

A novel gain-of-function Na1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy.

Voltage-gated sodium channel Na1.7 is a threshold channel in peripheral dorsal root ganglion (DRG), trigeminal ganglion, and sympathetic ganglion neurons. Gain-of-function mutations in Na1.

The Novel Activity of Carbamazepine as an Activation Modulator Extends from Na1.7 Mutations to the Na1.8-S242T Mutant Channel from a Patient with Painful Diabetic Neuropathy.

Neuropathic pain in patients carrying sodium channel gain-of-function mutations is generally refractory to pharmacotherapy. However, we have shown that pretreatment of cells with clinically achievable concentration of carbamazepine (CBZ; 30 M) depolarizes the voltage dependence of activation in some Na1.7 mutations such as S241T, a novel CBZ mode of action of this drug.

Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Na1.7 mutation that massively hyperpolarizes activation.

Sodium channel Na1.7 plays a central role in pain-signaling: gain-of-function Na1.7 mutations usually cause severe pain and loss-of-function mutations produce insensitivity to pain.

Na1.7 as a Pharmacogenomic Target for Pain: Moving Toward Precision Medicine.

Chronic pain is a global unmet medical need. Most existing treatments are only partially effective or have side effects that limit their use. Rapid progress in elucidating the contribution of specific genes, including those that encode peripheral voltage-gated sodium channels, to the pathobiology of chronic pain suggests that it may be possible to advance pain pharmacotherapy.

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial.

Background: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies.

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

Unlabelled: Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.

Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling.

Importance: There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable.

Objective: To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling.

Sodium Channels, Mitochondria, and Axonal Degeneration in Peripheral Neuropathy.

Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence).