Back to the Vascular Theory of Migraine?

Abstract & Commentary

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim and Bayer, and is on the speakers bureau for Boehringer Ingelheim.

Synopsis: Nitric oxide donor vasoactive compounds may trigger migraine headaches in migraineurs by promoting a massive increase in the mechanosensitivity of meningeal nociceptors, through an intermediate vasodilatory effect on meningeal vasculature.

Source: Zhang X, et al. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol 2013;73:741-750.

The mechanisms underlying the pain of migraine headache remain a mystery, with one possible component being increased mechanosensitivity, or sensitization, of nociceptive neurons that innervate the intracranial meninges. Nitroglycerin (NTG) and other nitric oxide (NO) donor vasoactive compounds can cause a delayed migraine-like headache in migraineurs. This delayed, NTG-induced headache responds to triptans and is associated with the inflammatory and neurotransmitter characteristics of migraine headaches. Systemic NTG administration and its delayed effects have been used as an experimental model of migraine headache in animals and humans. The finding that this NTG-induced headache is delayed for 3-4 hours after administration implies that NO acts as a trigger for a series of endogenous processes that eventually lead to pain sensitization.

The authors used a clinically relevant model of migraine triggering, infusion of NTG as an NO donor to examine the response properties of meningeal nociceptors. Single-unit recordings made in the trigeminal ganglion of male Sprague–Dawley rats were used to test changes in the activity and mechanosensitivity of meningeal nociceptors in response to administration of 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. Nociception induces upregulation of cellular mechanisms, such as phosphorylated extracellular signal-regulated kinase (pERK), so dural tissues were dissected free and subjected to pERK immunohistochemistry.

The 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 ERK phosphorylation in meningeal arteries and pharmacological blockade of meningeal ERK phosphorylation inhibited the development of NTG-evoked delayed meningeal nociceptor sensitization.


Despite extensive exploration, a detailed mechanistic explanation of migraine remains elusive. The authors concluded that development of delayed mechanical sensitization in meningeal nociceptors, evoked by the migraine trigger NTG, is potentially important as a neurophysiological correlate of migraine headache. They postulated that arterial ERK phosphorylation and its involvement in mediating the NTG-evoked delayed sensitization indicated a role of the meningeal vasculature in triggering migraine pain. However, as the authors point out, proving the importance of the meningeal vasculature in migraine pain is complicated, and intracranial meningeal vasodilatation, in isolation, may be but an intermediate step in nociceptor sensitization leading to the production of a migrainous headache. Systemic infusion of calcitonin gene-related peptide (CGRP) in migraineurs causes a delayed migrainous headache; however, CGRP is only associated with a slight vasodilatory effect. The administration of vasoactive intestinal peptide (VIP) does not trigger migraine headaches in migraineurs, despite its marked acute cephalic vasodilatatory effect. The differential effect of vasodilators in producing headache pain is perplexing, and
other cerebral vasodilators should be studied to determine which can induce a delayed sensitization of meningeal