Peripheral NaV1.7 modulation reveals divergent peripheral and central adaptations in persistent trigeminal pain
- 1University of Florida
Abstract
Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.
Related
- Sex-dependent endocannabinoid adaptations in supraspinal pain modulatory circuits after peripheral nerve injury
- Luminance and attentional modulation of size perception in peripheral vision: Response to Bedell and Johnson
- Does one size fit all? Comment on Jurkiewicz et al., Attentional modulation of size perception in peripheral vision.
- Multi-scale computational modeling of magnetoelectric nanoparticle-dispersed conductive nanofibers for peripheral nerve modulation.
- Euchromatin Peripheral Organization Follows Anterograde Signalling Under Anaesthetic Stress
BibTeX
@misc{allen2026peripheral,
title = {{Peripheral NaV1.7 modulation reveals divergent peripheral and central adaptations in persistent trigeminal pain}},
author = {H. N. Allen and N. K. Grabus and R. Khanna},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752059},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752059v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Peripheral NaV1.7 modulation reveals divergent peripheral and central adaptations in persistent trigeminal pain
AU - H. N. Allen
AU - N. K. Grabus
AU - R. Khanna
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752059
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752059v1
AB - Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.
ER -