Objectives In this study, we investigated the possible analgesic effects of Botulinum toxin type A (BoNT/A) on trigeminal neuralgia (TN). A modified TN mouse model was established by chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) in mice, and the possible roles of microglia toll-like receptor 2 (TLR2) and neuroinflammation was investigated. Methods Male C57BL/6 mice were divided into 3 groups, including sham group, vehicle-treated TN group and BoNT/A-treated TN group. Bilateral mechanical pain hypersensitivity, anxiety-like and depressive-like behaviors were evaluated by using von Frey test, open field, elevated plus-maze testing, and forced swimming test in mice, respectively. The mRNA or protein expression levels of toll-like receptors (TLRs), glia activation markers and proinflammatory factors in the trigeminal nucleus caudalis (TNC) were tested by RT-qPCR, immunofluorescence and Western blotting. We also tested the pain behaviors of TN in Tlr2−/− mice. Results We found that unilateral subcutaneous injection of BoNT/A into the whisker pad on the ipsilateral side of dIoN-CCI mice significantly attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors induced by dIoN-CCI surgery in mice. The dIoN-CCI surgery significantly up-regulated the expression of TLR2, MyD88, CD11b (a microglia marker), IL-1β, TNF-α and IL-6 in the ipsilateral TNC in mice, and BoNT/A injection significantly inhibited the expression of these factors. Immunostaining results confirmed that BoNT/A injection significantly inhibited the microglia activation in the ipsilateral TNC in dIoN-CCI mice. TLR2 deficiency also alleviated bilateral mechanical pain hypersensitivity and the up-regulation of MyD88 expression in the TNC of dIoN-CCI mice. Conclusion These results indicate that unilateral injection of BoNT/A attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors in dIoN-CCI mice, and the analgesic effects of BoNT/A may be associated with the inhibition of TLR2-mediated neuroinflammation in the TNC.
Background This study was designed to examine the therapeutic effects of Botulinum neurotoxin A (BoNT/A) on chronic migraine and to explore the potential mechanisms by using a mouse model of chronic migraine, which was established by repeated intraperitoneal (i.p.) injection with nitroglycerin (NTG).Methods NTG-induced basal and evoked mechanical hypersensitivity were evaluated using the von Frey filament test. Before the first injection of NTG, a single facial injection of BoNT/A was administered in the supraorbital region to explore its preventive effects on the development of chronic migraine in mice. The expression of calcitonin gene-related peptide (CGRP) and synaptosomal-associated protein25 (SNAP25) in the trigeminal ganglia (TG) and the trigeminal nucleus caudalis (TNC) were detected by Western blotting and immunostaining. Results Repeated administration of NTG resulted in basal and evoked mechanical hypersensitivity in mice. Single facial BoNT/A injection prevented the development of NTG-induced mechanical hypersensitivity in mice. Western blotting results revealed that peripheral BoNT/A injection decreased the NTG-induced upregulation of expression of CGRP and SNAP25 in the TGs and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes in the TNC. Immunostaining results revealed peripheral BoNT/A injection also decreased the NTG-induced upregulation of CGRP expression in the TNC.Conclusions Thus, these results indicate that single facial injection of BoNT/A may be a preventive treatment of chronic migraine, possible due to the inhibitory effect of BoNT/A on the expression of CGRP and SNAP25 in the TGs and NLRP3 inflammasomes in the TNC.
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