NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease

Abstract

Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel NaV1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective NaV1.7 blockade. Safinamide directly inhibited a NaV1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of NaV1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the NaV1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of NaV1.7 as a therapeutic target for Parkinsonian pain.

Hindmarsh-Rose neuronal network with spike-timing-dependent plasticity demonstrates coordinated reset neuromodulation for Parkinson's disease
S. Sharafi, J. Gilmer, M. Al Borno +1
bioRxiv27 May 2026PreprintCC BY-NC-NDFull textNeurosciencebioRxiv
Understanding when and how knowledge graphs add value to EHR-based clinical prediction across Parkinson's disease, multiple sclerosis, and chronic pain
A. Pathak, O. Stroganov, T. Ballinger +1
bioRxiv4 Oct 2026PreprintCC BY-NC-NDFull textBioinformatics & computational biologybioRxiv
Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.
C. Gentle, A. Kamesh, J. F. Madranges +12
bioRxiv14 Oct 2026PreprintCC BY-NC-NDFull textNeurosciencebioRxiv
Low-Dose Interleukin-2 Resolves Stress-Induced Chronic Sensitization Independent of Opioid Receptor Signaling
R. R. Simoes, S. Kraus, J. Zhang +7
bioRxiv1 Sep 2026PreprintCC BYFull textNeurosciencebioRxiv
Sex-dependent endocannabinoid adaptations in supraspinal pain modulatory circuits after peripheral nerve injury
L. Boullon, D. P. Finn, A. Llorente-Berzal
bioRxiv15 Oct 2026PreprintCC BY-NC-NDFull textNeurosciencebioRxiv

Cite

BibTeX RIS

BibTeX

@misc{nelson2026nav17dependent,
  title = {{NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease}},
  author = {T. S. Nelson and N. K. Grabus and H. N. Allen and A. Calderon-Rivera and S. Loya-Lopez and E. J. Rodriguez-Palma and A. L. Waters and E. Elhanafy and S. Shiers and I. Sankaranarayanan and K. Gomez and T. J. Price and R. J. Khanna},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.09.750469},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750469v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease
AU  - T. S. Nelson
AU  - N. K. Grabus
AU  - H. N. Allen
AU  - A. Calderon-Rivera
AU  - S. Loya-Lopez
AU  - E. J. Rodriguez-Palma
AU  - A. L. Waters
AU  - E. Elhanafy
AU  - S. Shiers
AU  - I. Sankaranarayanan
AU  - K. Gomez
AU  - T. J. Price
AU  - R. J. Khanna
PY  - 2026
DA  - 2026/09/09
PB  - bioRxiv
DO  - 10.64898/2026.09.09.750469
UR  - https://www.biorxiv.org/content/10.64898/2026.09.09.750469v1
AB  - Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel NaV1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective NaV1.7 blockade. Safinamide directly inhibited a NaV1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of NaV1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the NaV1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of NaV1.7 as a therapeutic target for Parkinsonian pain.
ER  -

Abstract

Related

Cite