Botulinum for Migraine Reaches Pain Receptors via Sutures

Daniel M. Keller, PhD

May 22, 2014

PHILADELPHIA — A key finding of a new study explains how injecting onabotulinumtoxinA (BoNT-A) into the scalp can prevent or reverse mechanical sensitization of meningeal nociceptors in migraine.

Researchers found that BoNT-A inhibits the suture branches of intracranial pain fibers when administered extracranially because these fibers have processes that protrude through the sutures in the calvaria.

"They come from the inside, and they terminate on the outside in the periosteum and the muscles. So if you put botulinum toxin along the suture lines it is taken [up] by these collateral branches, and it inhibits them," Rami Burstein, PhD, professor of anesthesia and neuroscience at Harvard Medical School and academic director of the comprehensive headache center and vice chairman for research affairs in the Anesthesia Department at Beth Israel Deaconess Medical Center in Boston, Massachusetts, told Medscape Medical News.

"And we think that over time, over several weeks...it progressively produces inhibition of the pain fibers inside the head," he said.

Speaking during an emerging science poster session here at the American Academy of Neurology (AAN) 66th Annual Meeting, Dr. Burstein said that when pain fibers get sensitized, they become responsive to mechanical stimulation, leading to the throbbing and intracranial hypersensitivity when patients sneeze, cough, bend over, or feel pulse pressure.

To test the hypothesis, Dr. Burstein and colleagues used a mouse model in which they stimulated meningeal nociceptors using some of the same inflammatory molecules that are secreted in the meninges during migraine (eg, histamine, serotonin, bradykinin, and prostaglandin E2).

Using electrophysiologic techniques, they then measured the firing frequency of different types of nerve fibers, having identified 43 C- and 36 Aδ-meningeal nociceptors. The effects of the inflammatory mediators on the fibers lasted for up to 20 hours.

BoNT-A was administered to the intracranial dura or to extracranial suture-receptive fields.

In his presentation, Dr. Burstein showed tracings of C-fiber meningeal nociceptor activity. BoNT-A did not reduce spontaneous activity in naive meningeal nociceptors, but it suppressed mechanical nociception induced by inflammatory substances in sensitized C- but not Aδ-meningeal nociceptors.

When given early, BoNT-A prevented sensitization of C- but not Aδ-fibers. When administered extracranially, it inhibited mechanical sensitivity of the suture branches of intracranial meningeal nociceptors.

He summarized that BoNT-A inhibits responses to mechanical pain but not to nonmechanical pain.

"What it means is if you get subcutaneous Botox [in the scalp] in a human, the mechanical pain threshold will go away, but you will still be able to feel," he said. "Botox is not making you numb...but it makes you feel less pain."

He said the implication of this finding is that BoNT-A has the potential to work beyond migraines for other somatic pains that are characterized by sensitization and mechanical pain, such as mechanical allodynia.

Dr. Burstein concluded that BoNT-A has a direct inhibitory effect on unmyelinated pain fibers and that the effect is selective for mechanical nociception; that is, it works on the receptor that is responsible for mechanical pain. That receptor has not yet been conclusively identified.

However, regardless of the specific receptor, BoNT-A interferes with the expression of high-threshold mechanosensitive ion channels on its surface and prevents their fusion into the nerve terminal, he added.

The study was funded in part by Allergan. Dr. Burstein has received personal compensation for activities with Allergan, GlaxoSmithKline, and Merck as a consultant or advisory board member and has received research support from Allergan, Merck, and GlaxoSmithKline.

American Academy of Neurology (AAN) 66th Annual Meeting. Emerging Science poster session abstract 002. Presented April 30, 2014.

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