Defining the Functional Role of Na1.7 in Human Nociception

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2019 Feb 24

PMID 30795902

Citations 82

Authors

Lucy A McDermott

Greg A Weir

Andreas C Themistocleous

Andrew R Segerdahl

Iulia Blesneac

Georgios Baskozos

Alex J Clark

Val Millar

Liam J Peck

Daniel Ebner

Irene Tracey

Jordi Serra

David L Bennett

Affiliations

Soon will be listed here.

Abstract

Loss-of-function mutations in Na1.7 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 Na1.7 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 Na1.7 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 Na1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na1.7 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.

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References

Emery E, Habib A, Cox J, Nicholas A, Gribble F, Woods C . Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations. J Neurosci. 2015; 35(20):7674-81. PMC: 4438121. DOI: 10.1523/JNEUROSCI.3935-14.2015. View

Okell T, Chappell M, Kelly M, Jezzard P . Cerebral blood flow quantification using vessel-encoded arterial spin labeling. J Cereb Blood Flow Metab. 2013; 33(11):1716-24. PMC: 3824178. DOI: 10.1038/jcbfm.2013.129. View

Salomons T, Iannetti G, Liang M, Wood J . The "Pain Matrix" in Pain-Free Individuals. JAMA Neurol. 2016; 73(6):755-6. DOI: 10.1001/jamaneurol.2016.0653. View

Minett M, Nassar M, Clark A, Passmore G, Dickenson A, Wang F . Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat Commun. 2012; 3:791. PMC: 3337979. DOI: 10.1038/ncomms1795. View

Goldberg Y, MacFarlane J, MacDonald M, Thompson J, Dube M, Mattice M . Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet. 2007; 71(4):311-9. DOI: 10.1111/j.1399-0004.2007.00790.x. View

Chambers S, Qi Y, Mica Y, Lee G, Zhang X, Niu L . Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat Biotechnol. 2012; 30(7):715-20. PMC: 3516136. DOI: 10.1038/nbt.2249. View

Herzog R, Cummins T, Ghassemi F, Dib-Hajj S, Waxman S . Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J Physiol. 2003; 551(Pt 3):741-50. PMC: 2343279. DOI: 10.1113/jphysiol.2003.047357. View

Serra J, Campero M, Ochoa J, Bostock H . Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin. J Physiol. 1999; 515 ( Pt 3):799-811. PMC: 2269177. DOI: 10.1111/j.1469-7793.1999.799ab.x. View

Lauria G, Hsieh S, Johansson O, Kennedy W, Leger J, Mellgren S . European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the.... Eur J Neurol. 2010; 17(7):903-12, e44-9. DOI: 10.1111/j.1468-1331.2010.03023.x. View

10.

Ramirez J, Habib A, Cox J, Themistocleous A, McMahon S, Wood J . Null mutation in SCN9A in which noxious stimuli can be detected in the absence of pain. Neurology. 2014; 83(17):1577-80. PMC: 4222855. DOI: 10.1212/WNL.0000000000000913. View

11.

Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G . A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004; 13(8):799-805. DOI: 10.1093/hmg/ddh096. View

12.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

13.

Fertleman C, Baker M, Parker K, Moffatt S, Elmslie F, Abrahamsen B . SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006; 52(5):767-74. DOI: 10.1016/j.neuron.2006.10.006. View

14.

Zhang X, Priest B, Belfer I, Gold M . Voltage-gated Na currents in human dorsal root ganglion neurons. Elife. 2017; 6. PMC: 5433841. DOI: 10.7554/eLife.23235. View

15.

Schwartzentruber J, Foskolou S, Kilpinen H, Rodrigues J, Alasoo K, Knights A . Molecular and functional variation in iPSC-derived sensory neurons. Nat Genet. 2017; 50(1):54-61. PMC: 5742539. DOI: 10.1038/s41588-017-0005-8. View

16.

Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork H, Handwerker H . Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol. 2003; 89(5):2441-8. DOI: 10.1152/jn.01139.2002. View

17.

Wang F, Julien D, Sagasti A . Journey to the skin: Somatosensory peripheral axon guidance and morphogenesis. Cell Adh Migr. 2013; 7(4):388-94. PMC: 3739816. DOI: 10.4161/cam.25000. View

18.

Zakrzewska J, Palmer J, Morisset V, Giblin G, Obermann M, Ettlin D . 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. Lancet Neurol. 2017; 16(4):291-300. DOI: 10.1016/S1474-4422(17)30005-4. View

19.

Krishnan A, Lin C, Park S, Kiernan M . Axonal ion channels from bench to bedside: a translational neuroscience perspective. Prog Neurobiol. 2009; 89(3):288-313. DOI: 10.1016/j.pneurobio.2009.08.002. View

20.

Groetzner P, Weidner C . The human vasodilator axon reflex - an exclusively peripheral phenomenon?. Pain. 2010; 149(1):71-75. DOI: 10.1016/j.pain.2010.01.012. View