ArticleThe journal of headache and pain2026
Botulinum toxin type A attenuates trigeminal neuralgia-like pain by suppressing CGRP release and modulating NaV1.7-associated signaling.
Article in The journal of headache and pain, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundTrigeminal neuralgia (TN) is a disabling facial pain disorder, and current treatments remain insufficient for a substantial proportion of patients. Botulinum toxin type A (BoNT/A) has shown therapeutic benefit in TN, but its peripheral analgesic mechanisms remain incompletely understood. We aimed to determine whether BoNT/A alleviates TN-like pain by modulating the calcitonin gene-related peptide (CGRP)-extracellular signal-regulated kinase (ERK)-NaV1.7 pathway in trigeminal ganglion neurons.
methodsTN-like pain was induced in mice by chronic constriction injury of the infraorbital nerve (CCI-ION). On postoperative day 14, BoNT/A (10 U) or saline was injected intradermally into the whisker pad. Evoked and spontaneous pain-like behaviors were assessed using von Frey testing, the Ugo Basile facial pain test, and spontaneous scratching recordings; anxiety-like behavior was evaluated using the elevated plus maze. Myelin pathology was examined by Luxol fast blue staining and transmission electron microscopy. CGRP, NaV1.7/NaV1.8, and ERK/MAPK signaling were examined in trigeminal ganglion neurons using immunofluorescence, Western blotting, RT-qPCR, ELISA, calcium-influx assays, and whole-cell patch-clamp recordings. Olcegepant and PD98059 were used to interrogate CGRP receptor- and ERK-dependent mechanisms.
resultsBoNT/A significantly attenuated CCI-ION-induced mechanical allodynia, increasing the facial withdrawal threshold from 0.11 to 1.29 g, and reducing spontaneous pain-like behaviors. BoNT/A also improved anxiety-like behavioral measures in CCI-ION mice. Histological and ultrastructural analyses shown partial amelioration of myelin pathology, accompanied by increased myelin basic protein expression and a lower g-ratio. Mechanistically, BoNT/A reduced CGRP-associated activity in TRPV1-positive trigeminal ganglion neurons, accompanied by lower serum CGRP levels and attenuated capsaicin-evoked calcium influx. These changes were associated with a preferential reduction in NaV1.7 membrane localization, without a comparable reduction in NaV1.8, and with a marked decrease in sodium current density, with peak sodium current reduced by 78.6%. Pharmacological inhibition of CGRP receptors or ERK phosphorylation reproduced the effects of BoNT/A on NaV1.7 membrane localization.
conclusionsThese findings suggest that BoNT/A alleviates CCI-ION-induced TN-like pain, at least in part, by suppressing CGRP-dependent ERK activation and subsequent NaV1.7 membrane recruitment in trigeminal ganglion neurons. The CGRP-ERK-NaV1.7 pathway may represent a peripheral mechanism of BoNT/A-mediated analgesia and a potential target for neuropathic facial pain. CLINICAL TRIAL NUMBER: Not applicable.
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