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Cited by 33Ion channel regulation and functionPain Mechanisms and TreatmentsIon Channels and Receptors

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

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Xie, Yu-Feng, Yang, Jane, Ratté, Stéphanie, Prescott, Steven A·2024·eLife
DOI 10.7554/elife.90960.3PMC PMC11060714

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Abstract

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel Na V 1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting Na V 1.7 pharmacologically have struggled. This may reflect the variable contribution of Na V 1.7 to nociceptor excitability. Contrary to claims that Na V 1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of Na V 1.3, Na V 1.7, and Na V 1.8. Selectively blocking one of those Na V subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on Na V 1.8 in acutely dissociated nociceptors but responsibility shifts to Na V 1.7 and Na V 1.3 by the fourth day in culture. A similar shift in Na V dependence occurs in vivo after inflammation, impacting ability of the Na V 1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different Na V subtypes exemplifies degeneracy – achieving similar function using different components – and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant Na V subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

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  • Selectively blocking one of those Na(V) subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed.

    “Selectively blocking one of those Na(V) subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [19]

    The Abstract says that blocking NaV1.7 becomes inconsequential when other NaV subtypes are abundant enough to maintain nociceptor excitability. The Discussion gives the broader condition: blocking an isoform matters when excitability depends on it, with channel inactivation also affecting that dependence. Thus the claim captures the role of other subtypes but overstates weak expression as the sole requirement. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • Similar physiological outputs can be produced by variable sets of component parameters.

    “similar physiological outputs can be produced by variable sets of component parameters [17][18][19][20]”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [19]

  • A similar shift in Na(V) dependence occurs in response to inflammation.

    “A similar shift in Na(V) dependence occurs in in response to inflammation.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [19]

  • Nociceptors can achieve similar excitability using different combinations of Na(V)1.3, Na(V)1.7, and Na(V)1.8 channels.

    “the authors argue that nociceptors can achieve similar excitability using different combinations of Na(V)1.3,Na(V)1.7, and Na(V)1.8channels.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [19]

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Authors
Xie, Y.-F., Yang, J., Ratté, S., & Prescott, S. A.
Affiliations
University of Toronto (CA)
Corresponding author
Prescott, Steven A
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-04-30
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.90960.3
PMC
PMC11060714
OpenAlex
W4388125863
Cited by
33
References
3
Citations by year
2026: 19 · 2025: 11 · 2024: 2 · 2023: 1
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • eLife (acceptedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Canadian Institutes of Health Research (FDN167276)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
nociceptor excitability, voltage-gated sodium channels, Nav1.7, Nav1.3, Nav1.8, pain insensitivity, inflammation, action potential
MeSH terms
Benzenesulfonamides, Action Potentials, Analgesics, Animals, Humans, Nociceptors, Pain, Phenyl Ethers, Sodium Channels, Mice, NAV1.7 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel

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