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J Neurosci. 2018 Nov 20. pii: 2433-18. doi: 10.1523/JNEUROSCI.2433-18.2018. [Epub ahead of print]

Resilience to Pain: A Peripheral Component Identified using induced Pluripotent Stem Cells and Dynamic Clamp.

Author information

1
Department of Neurology; Yale University, New Haven, CT.
2
Center for Neuroscience & Regeneration Research, VA Connecticut Healthcare System, West Haven, CT.
3
Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University, New Haven, CT.
4
Department of Neurology; Yale University, New Haven, CT stephen.waxman@yale.edu.

Abstract

Pain is a complex process that involves both detection in the peripheral nervous system and perception in the central nervous system. Individual-to-individual differences in pain are well-documented, but not well-understood. Here we capitalized on inherited erythromelalgia (IEM), a well-characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Nav1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain and an unaffected father). We show, first, that at least in some cases, relative sensitivity to pain can be modeled in subject-specific iPSC-derived sensory neurons in vitro; second, that in some cases, mechanisms operating in peripheral sensory neurons contribute to inter-individual differences in pain; and third, using Whole Exome Sequencing (WES) and dynamic clamp we show that it is possible to pinpoint a specific variant of another gene, KCNQ in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to inter-individual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model inter-individual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to inter-individual differences in pain.SIGNIFICANCE STATEMENTIndividual-to-individual differences in pain are well-documented, but not well-understood. In this study we show, first, that at least in some cases, relative sensitivity to pain can be modeled in subject-specific iPSC-derived sensory neurons in vitro; second, that in some cases, mechanisms operating in peripheral sensory neurons contribute to inter-individual differences in pain; and third, using Whole Exome Sequencing (WES) and dynamic clamp we show that it is possible to pinpoint a specific gene variant that modulates pain signaling and contributes to inter-individual differences in pain.

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