Migraine meets membrane trafficking

Abstract

Having a drug that works clinically, but without a clear mechanism, is like having a key that can be tried on many doors—eventually one will open, but what will be found? The paper by Burstein and colleagues (1) in this issue of Cephalalgia describes an unexpected connection between migraine and membrane trafficking associated with mechanical pain. In an elegant series of experiments, they show that onabotulinumtoxinA (BoNT-A) inhibits mechanical hyperalgesia, and proposed that it may act by preventing the insertion of mechanoreceptors at the plasma membrane. The authors used their well-established rat model of inflammatory agent-induced cranial pain to test the effect of BoNT-A on electrophysiological responses to mechanical stimulation. As an added bonus, they examined both intracranial and extracranial nociceptive branches of meningeal nociceptors, which was logical given that BoNT-A is injected extracranially. BoNT-A inhibited C-fiber responses to suprathreshold stimuli that could produce mechanical pain, but not responses to threshold non-pain stimuli. The remarkably long latency of hours for BoNT-A action is consistent with inhibition of mechanoreceptor translocation to the plasma membrane. This study is the first to test BoNT-A effects on nociceptive neurons believed to mediate migraine headache. As such, it takes us a step closer to understanding how this therapy may benefit migraine patients. While clinically proven effective for chronic migraine, the mechanism of action has been a mystery. Dogma predicted