Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors
Article first published online: 17 JUN 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 73, Issue 6, pages 741–750, June 2013
How to Cite
Zhang, X., Kainz, V., Zhao, J., Strassman, A. M. and Levy, D. (2013), Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol., 73: 741–750. doi: 10.1002/ana.23873
- Issue published online: 18 JUL 2013
- Article first published online: 17 JUN 2013
- Accepted manuscript online: 27 FEB 2013 03:05PM EST
- Manuscript Accepted: 15 FEB 2013
- Manuscript Revised: 4 JAN 2013
- Manuscript Received: 18 SEP 2012
- NIH National Institute of Neurological Disorders and Stroke. Grant Numbers: NS061116, NS077882, NS032534
- NIH National Institute on Alcohol Abuse and Alcoholism. Grant Number: AA020305
- National Headache Foundation
To examine changes in the response properties of meningeal nociceptors that might lead to migraine pain and examine endogenous processes that could play a role in mediating them using a clinically relevant model of migraine triggering, namely infusion of the nitric oxide (NO) donor nitroglycerin (NTG).
Single-unit recordings made in the trigeminal ganglion of rats were used to test changes in the activity and mechanosensitivity of meningeal nociceptors in response to administration of the migraine trigger NTG or another NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) at doses relevant to the human model of migraine headache. Immunohistochemistry and pharmacological manipulations were used to investigate the possible role of meningeal vascular signaling in mediating the responses of meningeal nociceptors to NO.
Infusion of NTG promoted a delayed and robust increase in the mechanosensitivity of meningeal nociceptors, with a time course resembling the development of the delayed migraine headache. A similar sensitization was elicited by dural application of NTG and SNAP. NTG-evoked delayed meningeal nociceptor sensitization was associated with a robust extracellular signal-regulated kinase (ERK) phosphorylation in meningeal arteries. Pharmacological blockade of meningeal ERK phosphorylation inhibited the development of NTG-evoked delayed meningeal nociceptor sensitization.
The development of delayed mechanical sensitization evoked by the migraine trigger NTG is potentially of great importance as the first finding of a neurophysiological correlate of migraine headache in meningeal nociceptors. The arterial ERK phosphorylation and its involvement in mediating the NTG-evoked delayed sensitization points to an important, yet unappreciated, role of the meningeal vasculature in the genesis of migraine pain. ANN NEUROL 2013;73:741–750