Treating Migraine through the Trigeminal Ganglion

Migraine is characterized by episodic, often disabling headache, associated with sensory, autonomic, central nervous system-related and cognitive symptoms. Research has established that various parts of the trigeminal system are responsible for peripheral symptoms of migraine. Treatment with corticosteroids reduces the symptoms of migraine, but the treatment is associated with long-term side effects.

It has also been previously established that Onabotulinumtoxin type A (BoNT-A, marketed by Allergan under the brand name Botox^®) has shown efficacy in the treatment of chronic migraine. BoNT-A was first found to be effective at treating migraine 15 years ago in conjunction with cosmetic treatments. But its exact mechanism of action still isn’t known. Clinicians suspect that it reduces proprioceptive signaling to the brainstem and interferes with the expression of mechanosensitive ion channels on meningeal nociceptors.

A study in the Journal of Headache and Pain looked at an organ culture method in decapitated rats to see if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG).* Organ culture is a way to induce an inflammatory response in the TG. “The advantage of this method is the study of neurons and satellite glial cells (SGCs) in their normal habitat,” the study authors note. A great deal of clinical evidence points to interaction between SGCs and the TG neurons. During organ culture, there is an inflammation response elicited with increased expression of cytokines and mitogen-activated protein kinases (MAPK).

The underlying hypothesis is that chronic migraine is associated with inflammation in various parts of the trigeminal system. Is it possible that BoNT-A might interfere with the expressional changes of the induced inflammation?

The study authors found that organ culture of the TG resulted in enhanced expression of calcitonin gene-related peptide (CGRP) and synaptosome-associated protein of 25 kDa (SNAP-25) in neurons and inducible nitric oxide synthase (iNOS) in SGCs. Co-incubation with mitogen activated kinase (EK1/2) inhibitor U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. “The overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG,” the study authors note. “We hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs.”

The researchers hope that a greater understanding of the mechanisms involved in nerve stimulation may suggest novel therapeutics. “The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations,” the study authors conclude.

*Note: The researchers disclose that author collaborators have received an unrestricted grant from Allergan and samples of Botox for this preclinical project.