Therapeutic use of botulinum toxin in migraine: mechanisms of action

Br J Pharmacol. 2014 Sep;171(18):4177-92. doi: 10.1111/bph.12763.


Migraine pain represents sensations arising from the activation of trigeminal afferents, which innervate the meningeal vasculature and project to the trigeminal nucleus caudalis (TNC). Pain secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the TNC. Such viscerosomatic convergence accounts for referral of migraine pain arising from meningeal afferents to particular extracranial dermatomes. Botulinum toxins (BoNTs) delivered into extracranial dermatomes are effective in and approved for treating chronic migraine pain. Aside from their well-described effect upon motor endplates, BoNTs are also taken up in local afferent nerve terminals where they cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, and prevent local terminal release. However, a local extracranial effect of BoNT cannot account for allthe effects of BoNT upon migraine. We now know that peripherally delivered BoNTs are taken up in sensory afferents and transported to cleave SNARE proteins in the ganglion and TNC, prevent evoked afferent release and downstream activation. Such effects upon somatic input (as from the face) likewise would not alone account for block of input from converging meningeal afferents. This current work suggests that BoNTs may undergo transcytosis to cleave SNAREs in second-order neurons or in adjacent afferent terminals. Finally, while SNAREs mediate exocytotic release, they are also involved in transport of channels and receptors involved in facilitated pain states. The role of such post-synaptic effects of BoNT action in migraine remains to be determined.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Botulinum Toxins / pharmacology*
  • Botulinum Toxins / therapeutic use
  • Humans
  • Migraine Disorders / drug therapy
  • Migraine Disorders / metabolism*
  • Neurons, Afferent / metabolism
  • Pain / drug therapy
  • Pain / metabolism
  • SNARE Proteins / metabolism


  • SNARE Proteins
  • Botulinum Toxins