A mouse model of classical trigeminal neuralgia via intradural compression of the trigeminal nerve

Abdulrahim, M.; Xu, R.; Chen, Y.; Nair, S.; Xu, Q.; Zhang, Y.; Das, O.; Gensler, R.; Feghali, J.; Ahmad, A. K.; Jackson, C.; Huang, J.; Comair, Y.; Bettegowda, C.; Dong, X.

doi:10.1101/2025.11.24.690061

bioRxiv · 10.1101/2025.11.24.690061

A mouse model of classical trigeminal neuralgia via intradural compression of the trigeminal nerve

Abdulrahim, M.·Xu, R.·Chen, Y.·Nair, S.·Xu, Q.·Zhang, Y.·Das, O.·Gensler, R.·Feghali, J.·Ahmad, A. K.·Jackson, C.·Huang, J.·Comair, Y.·Bettegowda, C.·Dong, X.

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Abstract

IntroductionTrigeminal neuralgia (TN) is a debilitating orofacial pain condition that adversely affects quality of life. Although heterogeneous, the most common form of TN is classical TN, characterized by paroxysmal bouts of pain in response to otherwise innocuous stimuli. It is believed that classical TN results from neurovascular compression of the trigeminal nerve. However, the underlying pathophysiology of TN is not well understood, thus limiting the development of targeted therapies. Current animal models lack translational relevance, particularly in their inability to replicate intradural nerve root compression, a core anatomic component of TN. MethodsWe developed a TN mouse model that achieves intradural nerve root compression via a retro-orbital approach confirmed by anatomic dissection and magnetic resonance imaging. To assess behavioral outcomes, we measured orofacial pain through facial wiping and interaction with a reward stimulus. Pharmacological responsiveness was tested using carbamazepine administration. Mechanistic studies included calcium imaging of trigeminal ganglia (TG), electrophysiologic recordings to measure resting membrane potential and rheobase, and immunohistochemical analysis of the TG. ResultsThe model elicited orofacial neuropathic pain, substantiated by increased facial wiping and reduced interaction with a reward stimulus, behaviors that suggest both spontaneous and evoked pain. Carbamazepine attenuated these behaviors, suggesting pharmacologic relevance to current TN treatment. Calcium imaging showed heightened spontaneous activity in the TG, and electrophysiologic recordings revealed an increased resting membrane potential and a reduced rheobase. Finally, immunohistochemical studies showed infiltration of CD45+ cells, demyelination and an increase in CGRP expression in the TG, supporting the presence of neuroinflammation after nerve root compression. ConclusionThese findings show that our approach replicates the anatomy and clinical presentation of classical TN in humans. This model may represent a new and robust platform for future mechanistic studies of TN and subsequent preclinical evaluation of therapies in mice.

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Abdulrahim, M., Xu, R., Chen, Y., Nair, S., Xu, Q., Zhang, Y., Das, O., Gensler, R., Feghali, J., Ahmad, A. K., Jackson, C., Huang, J., Comair, Y., Bettegowda, C., Dong, X.. 2025-11-26. A mouse model of classical trigeminal neuralgia via intradural compression of the trigeminal nerve. https://doi.org/10.1101/2025.11.24.690061

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