Central Effects of Peripherally Administered Botulinum Toxin: Relevance for Migraine Treatment

CNS Effects of Botulinum Toxin

Increases in trigeminal activation are observed during the period preceding a migraine attack (the preictal migraine phase), as shown by functional MRI (fMRI) studies comparing migraineurs to non-migraineurs. 1 This change in trigeminal activity is thought of as a ‘predictor’ of migraine attacks.

Cortical spreading depression (CSD), a biphasic electrophysiological phenomenon originating in the visual cortex, was shown to occur during visual auras that precede migraine attacks, and to lead to meningeal nociceptor activation, triggering activation of peripheral, then central neurons in the trigeminovascular pathway.2 CSD thus acts as a nociceptive stimulus, and migraine-associated pain which ensues is mediated through this meningeal trigeminovascular pathway.

Researchers at the University of California, San Diego sought to investigate how extracranial botulinum toxin (BoNT), shown to effectively treat chronic migraine pain, was also effective on migraine originating in the meninges, despite being administered peripherally. They presented their results at the American Headache Society 2016 Annual Meeting in San Diego.3

BoNT is composed of a heavy and light chain. The toxin undergoes membrane receptor-mediated endocytosis through its heavy chain4. Acidic environment in the endosome allows for cleavage of BoNT light chain and its export to the cytosol. There, BoNT light chain, an edopeptidase specific to SNARE (Soluble NSF Attachment protein Receptor) proteins, including VAMPs (Vesicle-Associated Membrane Proteins) cleaves these proteins. As SNAREs mediate fusion of synaptic vesicles with the synaptic terminal, their cleavage by BoNT blocks synaptic transmission.5

Based on results from a prior study4, researchers hypothesized that BoNT could mediate its central effects upon intradermal administration, by being taken up by somatic afferents and transported to the trigeminal ganglion (TG) and central terminals. They further hypothesized that, in terminals, BoNT would lead to cleavage of SNARE proteins, and further, that BoNT could also act trans-synaptically.

In order to test these hypotheses, mice were injected unilaterally with BoNT (1.5 U/40 ml) or saline in the supra-orbital region. After 3 days, capsaicin (2.5 mg/30 ml) was injected ipsi-laterally, either in the supra-orbital region or in the meninges. Capsaicin-induced nocisponsive behavior, assessed by number of ipsilateral face wiping was monitored. VAMP protein cleavage in the ipsilateral trigeminal ganglion and peripheral afferents, as well as activation of immediate early gene c-FOS in the ipsilateral trigeminal nucleus caudalis (TNC) were measured.

Pre-treatment with supraorbital BoNT was shown to reduce ipsilateral supraorbital capsaicin-induced nocisponsive behavior on the ipsilateral side, to cleave VAMP in the V1 region of the ipsilateral trigeminal nucleus, and to decrease c-FOS activation in the ipsilateral TNC. Ipsilateral supraorbital pre-treatment with BoNT also reduced ipsilateral meningeal capsaicin-evoked VAMP in the TG, and c-FOS activation in the TNC.

Authors concluded that peripheral cutaneous afferents take up BoNT, which is retrogradely transported to central terminals. There, the toxin, through cleavage of VAMP proteins, blocks neurotransmitter release, leading to a reduction in capsaicin-mediated activation of secondary order neurons. This study also supports a trans-synaptic action of BoNT on secondary order neurons or TG.

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1.Stankewitz A, Aderjan D, Eippert F, May A. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci. 2011;31(6):1937-43.

2.Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69(5):855-65.

3.Ramachandran R, Lam C, Yaksh T. Abstract PS47. Transport of Botulinum toxin in trigemino-somatic and trigemino-vascular afferents. Presented at: 2016 American Headache Society Annual Meeting. June 9-12, 2016; San Diego, CA.

4.Marino MJ, Terashima T, Steinauer JJ, Eddinger KA, Yaksh TL, Xu Q. Botulinum toxin B in the sensory afferent: transmitter release, spinal activation, and pain behavior. Pain. 2014;155(4):674-84.5.

5.Binz T, Sikorra S, Mahrhold S. Clostridial neurotoxins: mechanism of SNARE cleavage and outlook on potential substrate specificity reengineering. Toxins (Basel). 2010;2(4):665-82.