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Defining the Functional Role of Na V 1.7 in Human Nociception.

Authors :: McDermott LA
Weir GA
Themistocleous AC
Segerdahl AR
Blesneac I
Baskozos G
Clark AJ
Millar V
Peck LJ
Ebner D
Tracey I
Serra J
Bennett DL
Source :: Neuron [Neuron] 2019 Mar 06; Vol. 101 (5), pp. 905-919.e8. Date of Electronic Publication: 2019 Feb 19.
Publication Year :: 2019
Abstract: Loss-of-function mutations in Na <subscript>V</subscript> 1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how Na <subscript>V</subscript> 1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous Na <subscript>V</subscript> 1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that Na <subscript>V</subscript> 1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na <subscript>V</subscript> 1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade. VIDEO ABSTRACT.<br /> (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)