Hoffmann, T., Sharon, O., Wittmann, J. et al. (6 more authors) (2018) NaV1.7 and pain: contribution of peripheral nerves. Pain, 159 (3). pp. 496-506. ISSN 0304-3959
Abstract
The sodium channel NaV1.7 contributes to action potential generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to CNS the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin we found (1) a significantly lower prevalence of heat responsiveness to in normally mechanosensitive C-fibers, although (2) the rare heat responses appeared quite vigorous and (3) heat-induced CGRP release was normal. In biophysical respects, while electrical excitability, rheobase and chronaxy were normal (4) axonal conduction velocity was 20% slower than in congenic wildtype mice (5) and when challenged with double pulses (< 100 ms interval), the second action potential showed more pronounced latency increase (6). Upon prolonged electrical stimulation at 2 Hz, (7) activity-dependent slowing of nerve fiber conduction was markedly less and (8) was less likely to result in conduction failure of the mutant single-fibers. Finally, recording of compound action potentials from the whole saphenous nerve confirmed slower conduction and less activity-dependent slowing as well as the functional absence of a large subpopulation of C-fibers (9) in conditional Nav1.7 knock-outs. In conclusion, the clear deficits in somatic primary afferent functions shown in our study may be complemented by previously reported synaptic dysfunction and opioidergic inhibition, together accounting for the complete insensitivity to pain in the human mutants lacking Nav1.7.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 International Association for the Study of Pain. This is an author produced version of a paper subsequently published in Pain. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Voltage-gated sodium channels; Unmyelinated fibers; CGRP release; Compound action potential; Plantar test; von Frey test |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 15 Dec 2017 13:35 |
Last Modified: | 15 Dec 2023 16:00 |
Status: | Published |
Publisher: | Lippincott, Williams & Wilkins |
Refereed: | Yes |
Identification Number: | 10.1097/j.pain.0000000000001119 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125179 |