Recent advances for using human induced-pluripotent stem cells as pain-in-a-dish models of neuropathic pain.

Neuropathic pain is amongst the most common non-communicable disorders and the poor effectiveness of current treatment is an unmet need. Although pain is a universal experience, there are significant inter-individual phenotypic differences. Developing models that can accurately recapitulate the clinical pain features is crucial to better understand underlying pathophysiological mechanisms and find innovative treatments.

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain.

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.

A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several pore-forming voltage-gated sodium channel α subunits (Na) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease.

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.