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Abstract Details

Selective Inhibition of Meningeal Nociceptors by Botulinum Neurotoxin Type A (BoNT-A): Therapeutic Implications to Migraine and Other Pains
Headache
(-)
002
Migraine is a complex neurological disorder. While factors that predispose an individual to migraine attacks and those leading to attack initiation are not fully understood, it is generally believed that the headache depends on activation of trigeminal nociceptors supplying intracranial meninges. Accordingly, we hypothesized that effective peripherally-administered migraine prophylactics must reduce excitability of meningeal nociceptors. In this study, we assessed BoNT-A effects on different classes of na茂ve and sensitized meningeal nociceptors.
Using electrophysiological techniques, we identified 43 C- and 36 A-delta-meningeal nociceptors in the trigeminal ganglion, and measured their spontaneous and evoked firing before and after BoNT-A administration to intracranial dura and extracranial suture receptive fields. BoNT-A effects were studied in na茂ve units, in units sensitized by inflammatory soup (IS) prior to BoNT-A administration, and in units in which BoNT-A was administered hours before induction of sensitization by the IS.
BoNT-A inhibited C- but not A-delta-meningeal nociceptors. When applied to na茂ve C-units, BoNT-A inhibited responses to mechanical stimulation of the dura with suprathreshold forces. When applied after IS-induced sensitization, BoNT-A reversed the mechanical hypersensitivity. When applied before IS, BoNT-A prevented the development of IS-induced mechanical hypersensitivity. When applied extracranially, to the suture branch of the meningeal nociceptor, BoNT-A inhibited the mechanical responsiveness of the suture branch but not dural axon. In contrast, BoNT-A did not inhibit C-unit responses to mechanical stimulation of the dura with threshold forces, or their spontaneous activity.
The study provides direct evidence for BoNT-A ability to inhibit mechanical nociception in peripheral trigeminovascular neurons. The preferential suppression of responses to suprathreshold mechanical simulation suggests that BoNT-A inhibits high-threshold mechanosensitive ion channels linked to mechanical pain. We propose a mechanism whereby BoNT-A interferes with SNARE-mediated surface expression of relevant receptors, thus preventing fusion into the nerve terminal membrane.
Authors/Disclosures
Rami Burstein, PhD (Beth Isreal Deacones Medical Center) Dr. Burstein has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Burstein has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Dr. Reddy. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurolief. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Percept. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Theranica. The institution of Dr. Burstein has received research support from Allergan. The institution of Dr. Burstein has received research support from Teva. The institution of Dr. Burstein has received research support from Eli Lilly. The institution of Dr. Burstein has received research support from Dr. Reddy.
No disclosure on file
Matthias Kant (Sygehus Soenderjylland) Matthias Kant has nothing to disclose.
Dan Levy, PhD (Harvard Institutes of Medicine) No disclosure on file
K. Roger Aoki, PhD (Allergan, Inc.) No disclosure on file
Mitchell F. Brin, MD, FAAN (Abbvie / UC Irvine) Dr. Brin has received personal compensation for serving as an employee of Allergan. Dr. Brin has stock in Allergan.