293 Spontaneous Impulse Generation in C‐nociceptors of Familial Erythromelalgia (Fe) Patients

Uyanık, Orkun; Quiles, Cristina; Bostock, Hugh; Dib‐Hajj, Sulayman D.; Fischer, Tanya; Tyrrell, Lynda; Sg, Waxman; Serra, Jordi

doi:10.1016/j.ejpain.2007.03.308

Cited by 1 publication

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“…Overexpression of the F1449V, V400M, I848T, and S241T Nav1.7 mutations in rodent dorsal root ganglion neurons has also been reported to reduce current threshold and increase the frequency of firing of dorsal root ganglion neurons in response to graded stimuli (21)(22)(23). The pathophysiological consequence of IEM on neuronal excitability has been examined in clinical microneurography studies (24,25). One subject with the I848T mutation demonstrated increased C-fiber nociceptor excitability (26).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia

et al. 2016

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One sentence summary: Bench to bedside translation using iPSC to characterise phenotype and pharmacology in primary erythromelalgia, an inherited chronic pain condition. ABSTRACTIn common with other chronic pain conditions, inherited erythromelalgia (IEM) represents a significant unmet medical need. The peripherally expressed SCN9A encoded sodium channel Nav1.7 plays a critical role in IEM with gain-of-function leading to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. In five carefully phenotyped IEM patients, a novel highly potent and selective Nav1.7 blocker reduced heat-induced pain in the majority of subjects. In four of the five subjects we used induced pluripotent stem cell (iPSC) technology to create sensory neurons which uniquely emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the iPSC-derived sensory neuron hyperexcitability we saw a trend towards a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, this translational approach is likely to have broader utility to a wide range of pain and sensory conditions. This emphasizes the use of iPSC approaches to bridge between clinical and preclinical studies, enabling greater understanding of a disease and the response to a therapeutic agent in defined patient populations.

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Section: Discussionmentioning

confidence: 99%

“…The pathophysiological consequence of IEM on neuronal excitability has been examined in clinical microneurography studies 23,24 . One subject with the I848T mutation demonstrated increased C-fiber nociceptor excitability 25 .…”

Section: Scn9amentioning

confidence: 99%