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Peer-reviewedCC BY 4.0Cell Reports Medicine

Disruption of the Nav1.8/Ankyrin-3 interaction in nociceptors reduces pathological pain-like behaviors in mice

  • Rasheen Powell1,2
  • Xiangsunze Zeng1,2
  • Bruna Lenfers Turnes1,2
  • Hyoung Woo Kim1,2
  • Veselina Petrova1,2
  • Selwyn S. Jayakar1,2
  • Emily Shea1
  • Keunjung Heo1,2
  • Emma Cropper1
  • Maryam Arab1
  • Georgios Kimourtzis1,2
  • Juan A. Oses-Prieto3
4 more authors
  • Alma L. Burlingame3
  • Stephen G. Waxman4
  • Sulayman D. Dib-Hajj4
  • Clifford J. Woolf1,2
4 affiliations
  1. 1F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA
  2. 2Department of Neurobiology, Harvard Medical School, Boston, MA, USA
  3. 3Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
  4. 4Department of Neurology, Yale School of Medicine, New Haven, CT, USA
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Abstract

Treating chronic neuropathic pain is challenging due to its complex pathophysiology. Persistent changes in the somatosensory system prolong heightened states of stimulus-evoked and spontaneous pain. Nociceptor dorsal root ganglion (DRG) neurons are key contributors to neuropathic pain due to pathological plasticity following injury, leading to spontaneous ectopic and stimulus-evoked firing. Preclinical strategies to inhibit Nav1.8, a nociceptor-specific voltage-gated sodium channel, are successful in reducing neuropathic pain but have yet to produce similar results in clinical settings. Here, we evaluate the pharmacotherapeutic potential of the Nav1.8/Ank3 interaction in neuropathic pain, utilizing electrophysiology, biochemistry, and proteomic approaches. We report that Nav1.8/Ank3 interactions are necessary for maintaining pathological nociceptor hyperexcitability in neuroma pain and that inhibition of this interaction with a short lipidated peptide (SLiP) is sufficient to alleviate neuropathic pain-like behaviors in mice. This work highlights the value of reevaluating targets for pharmacological intervention to produce analgesia specific to pathological states.

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Cite

BibTeXRIS
BibTeX
@article{powell2026disruption,
  title = {{Disruption of the Nav1.8/Ankyrin-3 interaction in nociceptors reduces pathological pain-like behaviors in mice}},
  author = {Rasheen Powell and Xiangsunze Zeng and Bruna Lenfers Turnes and Hyoung Woo Kim and Veselina Petrova and Selwyn S. Jayakar and Emily Shea and Keunjung Heo and Emma Cropper and Maryam Arab and Georgios Kimourtzis and Juan A. Oses-Prieto and Alma L. Burlingame and Stephen G. Waxman and Sulayman D. Dib-Hajj and Clifford J. Woolf},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.xcrm.2026.103090},
  url = {https://doi.org/10.1016/j.xcrm.2026.103090},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Disruption of the Nav1.8/Ankyrin-3 interaction in nociceptors reduces pathological pain-like behaviors in mice
AU  - Rasheen Powell
AU  - Xiangsunze Zeng
AU  - Bruna Lenfers Turnes
AU  - Hyoung Woo Kim
AU  - Veselina Petrova
AU  - Selwyn S. Jayakar
AU  - Emily Shea
AU  - Keunjung Heo
AU  - Emma Cropper
AU  - Maryam Arab
AU  - Georgios Kimourtzis
AU  - Juan A. Oses-Prieto
AU  - Alma L. Burlingame
AU  - Stephen G. Waxman
AU  - Sulayman D. Dib-Hajj
AU  - Clifford J. Woolf
PY  - 2026
DA  - 2026/10/06
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103090
UR  - https://doi.org/10.1016/j.xcrm.2026.103090
AB  - Treating chronic neuropathic pain is challenging due to its complex pathophysiology. Persistent changes in the somatosensory system prolong heightened states of stimulus-evoked and spontaneous pain. Nociceptor dorsal root ganglion (DRG) neurons are key contributors to neuropathic pain due to pathological plasticity following injury, leading to spontaneous ectopic and stimulus-evoked firing. Preclinical strategies to inhibit Nav1.8, a nociceptor-specific voltage-gated sodium channel, are successful in reducing neuropathic pain but have yet to produce similar results in clinical settings. Here, we evaluate the pharmacotherapeutic potential of the Nav1.8/Ank3 interaction in neuropathic pain, utilizing electrophysiology, biochemistry, and proteomic approaches. We report that Nav1.8/Ank3 interactions are necessary for maintaining pathological nociceptor hyperexcitability in neuroma pain and that inhibition of this interaction with a short lipidated peptide (SLiP) is sufficient to alleviate neuropathic pain-like behaviors in mice. This work highlights the value of reevaluating targets for pharmacological intervention to produce analgesia specific to pathological states.
SN  - 2666-3791
ER  -