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Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.

ABSTRACT: Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 ?l) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 ?l of 0.5mM solution) or meningeal capsaicin (4 ?l of 0.35 ?M). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.

SUBMITTER: Ramachandran R

PROVIDER: S-EPMC4458441 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.

Ramachandran Roshni R Lam Carmen C Yaksh Tony L TL

Neurobiology of disease 20150506

Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received ...[more]

PMID: 25958249

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Project description:Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18-65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9-12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (-26.9% versus -20.5%; difference -6.4%; 95% confidence interval: -15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were -6.2 versus -7.0 (difference: 0.8; 95% confidence interval: -1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA.

Dataset Information

Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.

Publications

Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.

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