engleski

Activity of botulinum toxin type A in cranial dura: implications for treatment of migraine and other headaches

BACKGROUND AND PURPOSE: Although botulinum toxin type A (BoNT/A) is approved for chronic migraine treatment, its mechanism of action is still unknown. Dural neurogenic inflammation (DNI) commonly used to investigate migraine pathophysiology can be evoked by trigeminal pain. Here we investigated the reactivity of cranial dura to trigeminal pain, and the mechanism of BoNT/A action on DNI. EXPERIMENTAL APPROACH: Since temporomandibular disorders are highly comorbid with migraine we employed a rat model of temporomandibular joint (TMJ) inflammation induced by complete Freund's adjuvant (CFA). The rats were treated with BoNT/A injections or sumatriptan per os. DNI was investigated by Evans blue-plasma protein extravasation, cell histology and calcitonin gene-related peptide (CGRP) radioimmunoassay. BoNT/A enzymatic activity in dura was assessed by cleaved synaptosomal-associated protein 25 (SNAP-25) immunohistochemistry. KEY RESULTS: BoNT/A and sumatriptan reduced the CFA-evoked peripheral allodynia and DNI. BoNT/A prevented the inflammatory cell infiltration, and counteracted the increase of CGRP levels in dura. After toxin peripheral application, BoNT/A-cleaved SNAP-25 colocalized with CGRP in intracranial dural nerve endings. Injection of axonal transport blocker colchicine into trigeminal ganglion prevented the occurrence of cleaved SNAP-25 in dura. CONCLUSIONS AND IMPLICATIONS: Apparently, pericranially injected BoNT/A is taken up by local sensory nerve endings, axonally transported to trigeminal ganglion, and transcytosed to dural afferents. Colocalization of cleaved SNAP-25 and migraine mediator CGRP in dura suggests that BoNT/A may prevent DNI by suppressing the CGRP transmission. This might explain BoNT/A action in TMJ inflammation as well as in migraine and some other headaches.

axonal transport ; botulinum toxin type A ; calcitonin gene-related peptide ; dural neurogenic inflammation ; migraine

nije evidentirano