Reconsidering the Vascular Hypothesis of Migraine Pathophysiology
Triptans and the Role of 5-HT in Migraine
Though its specific actions are unclear, the role of 5-hydroxytryptamine (5-HT) in migraine is well accepted and is the basis of the most commonly used migraine therapies. Triptans represent up to 80% of medications prescribed for migraine treatment, though studies have shown a lack of efficacy in more than half of patients taking them.<sup>4</sup> Additionally, triptans are contraindicated for patients with cardiovascular disease, and because chronic use of these agents can lead to medication-overuse headache (MOH), they are not appropriate for daily use or as a preventive measure.<sup>5</sup> Drugs that may be prescribed off-label as a migraine prophylactic, such as topiramate and certain beta-blockers and antidepressants, carry the risk of serious adverse effects such as vomiting, impaired cognition, and withdrawal symptoms, and they are only effective in approximately half of patients, according to a 2012 study.<sup>6,7</sup>
Emerging Migraine Therapies
The multiple limitations associated with triptans highlight the pressing need for the development of novel migraine therapies. In recent studies, selective 5-HT-<sub>1F</sub> agonists such as lasmiditan have shown promise as abortive migraine therapies. A 2010 paper published in <i>Cephalgia</i>, for instance, reported that lasmiditan “potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis)” in 2 rodent models.<sup>8</sup> The same paper notes that in vitro studies have revealed that, compared to other 5-HT receptor agonists, lasmiditan demonstrated higher selectivity for the 5-HT(1F) receptor over other 5-HT(1) receptor subtypes, and it did not induce contraction of rabbit saphenous vein rings, which serves as a surrogate marker for human coronary artery constriction. Another promising treatment approach is the direct targeting of calcitonin gene-related peptide (CGRP), which has been found to be elevated during acute migraine and to trigger attacks when administered to migraineurs.<sup>9</sup> In phase 2 clinical trials, monoclonal antibodies to CGRP and its receptor led to significantly fewer migraine days, and phase 3 clinical trials investigating their efficacy in migraine prevention and treatment are now underway.<sup>10-13</sup>
Blood Vessel Anatomy and the Role of Endothelial Cells
The tunica media, the middle layer of the blood vessel, contains vascular smooth muscle cells that have been found to regulate vascular tone. The primary focus in migraine, however, has centered on endothelial cells, which comprise the tunica intima, the innermost layer of the blood vessel. These cells have direct contact with blood in the lumen and help to regulate numerous functions, including cell-cell barrier maintenance, vascular tone and remodeling, blood coagulation, and more, and they express various proteins such as growth factors, coagulants/anticoagulants, hormones, and cytokines.<sup>14-17</sup> Such findings indicate that the function of the blood vessel extends beyond contraction and dilation, and that it may coordinate complex signaling between multiple cell types. “Dysregulation of any part of this vascular signaling process may contribute to migraine pathology,” the authors of the <i>Neuroscience</i> review wrote.<sup>3</sup>
Role of the Hypothalamus in Migraine (Part I)
It has been proposed that migraine may originate in the hypothalamus, which has extensive connections in the central nervous system and helps to maintain homeostasis via control of the endocrine system and coordination of autonomic nervous system activity. Among the many physiologic functions of the hypothalamus, it is involved in trigeminal nociceptive signaling, a type of afferent sensory input that is essential to migraine pain.<sup>18</sup> The symptoms commonly reported by migraine patients – impaired sleep, changes in mood and appetite – involve dysfunction of the systems that the hypothalamus helps to regulate. Hypothalamic activation has been observed during migraine in positron emission tomographic and functional magnetic resonance imaging studies, further suggesting a central role for the hypothalamus in migraine pathophysiology.<sup>19,20</sup> In addition, the observation that women experience migraines at a 3-fold rate compared to men implicates hypothalamic regulation of hormonal cycles in women as contributing to migraine. Results of several studies suggest that the “increased incidence of migraine in women may be due in part to the effects of hypothalamic regulation of female hormones such as estradiol on endothelial cells,” as described in the <i>Neuroscience</i> review.<sup>3</sup>
Role of the Hypothalamus in Migraine (Part II)
Pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal polypeptide (VIP), and nitric oxide (NO) activate alternative signaling pathways in blood vessels independent of any potential migraine-associated vasodilation. Vasoactive intestinal peptide/ pituitary adenylate cyclase-activating polypeptide receptor-1 (VPAC1R) and VPAC2 receptors are expressed in various cell types, including endothelial cells, and these receptors demonstrate equal affinity for both VIP and PACAP.<sup>21,22</sup> A model of ischemia revealed that VIP led to increased angiogenesis via increased expression and secretion of vascular endothelial growth factor (VEGF) in endothelial cells, and because mediators of angiogenesis are believed to influence chronic inflammation, inflammatory pain may also be influenced by angiogenic signaling. Such findings “suggest that hypothalamic regulation of parasympathetic tone may activate vascular endothelial cell signaling pathways known to contribute to inflammatory pain” and that the hypothalamus may contribute to migraine “via endothelial cell-dependent signaling pathways independent of vasodilation,” though the mechanisms pertaining to specific migraine symptoms are not clear.<sup>3</sup>
Cortical Spreading Depression (Part I)
The sudden loss of membrane resistance and ionic gradients result in cortical spreading depression (CSD), which is characterized by the depolarization of neuronal and glial membranes. Because the rate of aura spread across the primary visual cortex during migraine corresponds to the velocity of signal propagation of CSD (approximately 2 to 5 mm/min), it may be that the wave neuronal excitation/inhibition contributes to migraine aura. This suggestion has been supported by recent imaging studies.<sup>23,24</sup> However, despite its suspected role as the basis for aura, other data indicate that it is unlikely that CSD is a direct cause of headache but may influence its development through the release of substances that activate/sensitize meningeal afferents of the trigeminal nerve.<sup>25</sup> Cerebral blood flow increases in order to restore ionic gradients and neuronal function affected by CSD, followed by a reduction in blood flow and oxygen that results in tissue hypoxia.<sup>25,26</sup>
Cortical Spreading Depression (Part II)
In response to this increase in cerebral blood flow, it is believed that cortical neurons release neurotransmitters such as NO, carbon monoxide, adenosine, and others. These molecules have a direct impact on endothelial signaling pathways independent of vascular tone.<sup>27</sup> “Moreover, the close association between cerebral blood vessels and neurons… facilitates 2-way communication between cortical neurons and endothelial cells comprising the blood vessels,” the authors of the <i>Neuroscience</i> review stated.<sup>3</sup> Endothelial cells can respond to substances released by neurons and vice versa. Arterial endothelial cells, for example, synthesize and store peptides including CGRP, and the endothelial release of this particular peptide may lead to an increase in cortical neuronal excitability.<sup>28</sup> “Thus, due to neurovascular mechanisms that contribute to neuronal hyperexcitability (e.g. endothelial cell release of CGRP), sensory stimulation in a specific cortical region that would otherwise go undetected in non-migraine patients (e.g. somatosensory events) may trigger a CSD event and aura in migraineurs.”<sup>3</sup>
Meningeal Afferents (Part I)
Inflammatory mediators that sensitize primary afferent nociceptors are increased during migraine. Likely as a result of neurogenic meningeal inflammation, dural mast cells, macrophages, and other immune cells release proinflammatory mediators known to sensitize meningeal nociceptors, such as 5-HT, histamine, prostaglandins, and cytokines.<sup>29</sup> In addition to neuronal receptors, non-neuronal cell types may also be involved in the sensitizing actions of inflammatory cytokines. For example, it has been found that “local application of TNF-α to the meninges evokes TNF receptor-mediated activation of p38 MAP kinase in dural blood vessels, and that the p38 antagonist SB203580 inhibits TNF-α-mediated meningeal afferent sensitization,” and additional factors released by endothelial cells, such as endothelin-1 (ET-1) and c-type natriuretic peptide (CNP), may also contribute to meningeal afferent sensitization.<sup>30</sup>
Meningeal Afferents (Part II)
There is also the possibility that changes in metabolic demand or mechanical stimulation cause the release of adenosine triphosphate from neurons and other vascular cells during migraine. As an example, in addition to vasodilation mediated by NO, meningeal afferent sensitization may also be mediated by NO released from endothelial cells. Recent studies show that NO donors that have been implicated in migraine promote delayed sensitization of meningeal nociceptors and extracellular signal-regulated kinase (ERK) phosphorylation in meningeal arteries, and the inhibition of ERK phosphorylation blocked NO donor nitroglycerin-mediated afferent sensitization.<sup>31</sup> In other findings, purinergic receptors were found to mediate increases in the endothelial cell surface expression of molecules involved in the recruitment of immune cells, and these immune cells release proinflammatory mediators that further amplify the sensitization of meningeal afferents.<sup>32,33</sup> “Taken together, vasodilation may be an epiphenomenon that has previously overshadowed concurrent endothelial cell-mediated signaling pathways contributing to sensitization of meningeal afferents and migraine pain,” the review concluded.<sup>3</sup>
Though migraine is the third most prevalent disease in the world,1 the lack of clarity regarding its underlying mechanisms limits the development of new treatments. The role of cerebral and meningeal arterial vasodilation as the primary migraine trigger, which was widely accepted for decades, has been refuted by a growing body of research. The authors of a 2013 study, for example, concluded that vasodilation does not cause migraine based on their findings that migraine pain was not associated with significant dilation of the extracranial arteries.2 In light of such findings, experts have turned their focus toward the potential role of the nervous system in migraine pathophysiology, and "it is likely that migraine is a consequence of dysfunctional neuronal networks, as certain neurological symptoms of migraine cannot be explained solely by the vascular model of headache," wrote the authors of a recent review published in Neuroscience on the topic.3 They examine evidence suggesting that blood vessels do contribute to migraine development, though perhaps via a mechanism other than vasodilation.
1. Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. J Headache Pain. 2013;14(1):1. doi: 10.1186/1129-14-1
2. Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-461.
3. Jacobs B, Dussor G. Neurovascular contributions to migraine: moving beyond vasodilation. Neuroscience. 2016;338:130-144.
4. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT[1B/1D] agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):1668-1675.
5. Kristoffersen ES, Lundqvist C. Medication-overuse headache: a review. J Pain Res. 2014;7:367-378.
6. Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet. 2010;376(9741):645-655.
7. Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs. 2012;26(5):375-382.
8. Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30(10):1159-1169.
9. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54-61.
10. Dodick DW, Goadsby PJ, Silberstein SD, et al; ALD403 Study Investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13(11):1100-1107.
11. Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13(9):885-892.
12. Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1081-1090.
13. Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1091-1100.
14. Breier G, Risau W. The role of vascular endothelial growth factor in blood vessel formation. Trends Cell Biol. 1996;6(12):454-456.
15. Stern D, Nawroth P, Handley D, Kisiel W. An endothelial cell-dependent pathway of coagulation. Proc Natl Acad Sci U S A. 1985;82(8):2523-2527.
16. Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki T. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl. 1988;6(4):S188-S191.
17. Mantovani A, Sozzani S, Introna M. Endothelial activation by cytokines. Ann N Y Acad Sci. 1997;832:93-116.
18. Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache. 2007;47(6):951-962.
19. Afridi SK, Giffin NJ, Kaube H, et al. A positron emission tomographic study in spontaneous migraine. Arch Neurol. 2005;62(8):1270-1275.
20. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic activation in spontaneous migraine attacks. Headache. 2007;47(10):1418-1426.
21. Borsani E, Giovannozzi S, Cocchi MA, Boninsegna R, Rezzani R, Rodella LF. Endothelial nitric oxide synthase in dorsal root ganglia during chronic inflammatory nociception. Cells Tissues Organs. 2013;197(2):159-168.
22. Zhou CJ, Shioda S, Yada T, Inagaki N, Pleasure SJ, Kikuyama S. PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways. Curr Protein Pept Sci. 2002;3(4):423-439.
23. Hansen JM, Baca SM, Vanvalkenburgh P, Charles A. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain. 2013;136(Pt 12):3589-3595.
24. Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9(11):637-644.
25. Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69(5):855-865.
26. Shinohara M, Dollinger B, Brown G, Rapoport S, Sokoloff L. Cerebral glucose utilization: local changes during and after recovery from spreading cortical depression. Science. 1979;203(4376):188-190.
27. Takano T, Tian GF, Peng W, KA, et al. Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci. 2007;10(6):754-762.
28. Dalvi S, Nguyen HH, On N, et al. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors. J Neurochem. 2015;135(5):867-879.
29. Yan J, Melemedjian OK, Price TJ, Dussor G. Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6). Mol Pain. 2012;8:6.
30. Zhang XC, Kainz V, Burstein R, Levy D. Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain. 2011;152(1):140-149.
31. Zhang X, Kainz V, Zhao J, Strassman AM, Levy D. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol. 2013(6);73:741-750.
32. Seiffert K, Ding W, Wagner JA, Granstein RD. ATPgammaS enhances the production of inflammatory mediators by a human dermal endothelial cell line via purinergic receptor signaling. J Invest Dermatol. 2016; 126(5):1017-1027.
33. Seye CI, Yu N, Gonzalez FA, Erb L, Weisman GA. The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1 expression through interaction with VEGF receptor-2 (KDR/Flk-1). J Biol Chem. 2004;279(34):35679-35686.
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