Neurobiological Basis of Migraine

Turgay Dalkara, Michael A. Moskowitz, Turgay Dalkara, Michael A. Moskowitz

• Publisher: Wiley-Blackwell
• Year: 2017
• Print ISBN: 9781118967195
• eBook ISBN: 9781118967201
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Published with the New York Academy of Sciences

A timely, broad-rangingexploration of the neurobiological basis and molecular mechanismsof migraines

Migraines impact the lives of a significant portion of the world's population, afflicting sufferers with severe pain, nausea, and often visual impairment. The WHO views migraines as an important public health issue, and ranks them in its top twenty most disabling illnesses. Neurobiological Basis of Migraine reviews the latest advances made in our understanding of the primary basic mechanisms of migraine headache and provides valuable insights into how these findings are being translated into novel treatment and prevention strategies around the world.

Written for researchers and clinicians alike, the book features edited contributions from distinguished experts in the field, taking a focused, yet wide-ranging approach to the subject. It begins by exploring the pathways and networks mediating migraine headaches, their underlying physiological mechanisms, characteristics of visceral pain, and the concept of dural neurogenic inflammation. From there the authors delve into the mechanisms sustaining the head pain and photophobia associated with migraines, and they review the pharmacology of newly discovered migraine treatments. These basic chapters are followed by clinical and genetic studies linking to key issues, including cortical spreading depression, ion channels, transporters, and epilepsy.

• Reviews of the latest advances in our understanding of the neurobiological basis of migraine
• Translates important research findings from around the globe into novel treatments strategies currently being investigated
• Provides researchers and clinicians with a deep understanding of the primary mechanisms of migraine from migraine modeling to clinical applications
• Includes contributions by many of the most respected researchers in the field, world-wide
• Discusses exciting recent developments in migraine mutations and their role in CSD, as well as the role of CSD in aura and trigeminal activation

Timely, comprehensive, and authoritative, Neurobiological Basis of Migraine is an indispensable working resource for clinicians and migraine, headache, and pain researchers, including neurobiologists, neuropharmacologists, neurologists, and vascular neurobiologists, as well as graduate students in those fields who are involved in researching migraine headaches.

Part I
Anatomy and physiology

Chapter 1
Functional anatomy of trigeminovascular pain

Karl Messlinger¹ and Mária Dux²

¹Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

²Department of Physiology, University of Szeged, Szeged, Hungary

1.1 Anatomy of the trigeminovascular system

The trigeminal system, consisting of afferent nerve fibers mostly arising from the trigeminal ganglion, conveys sensory information from extra- and intracranial structures to the central nervous system via the fifth cranial nerve. The term “trigeminovascular system” has been formed to describe the close morpho-functional relationship of trigeminal afferents with intracranial blood vessels, originally in the context of vascular headaches (Moskowitz, 1984). Nowadays, the term may be extended to extracranial tissues, as well as to the central projections of trigeminal afferents into the trigeminal nuclear brainstem complex, as specified below.

1.1.1 Vascularization and innervation of the dura mater encephali

Large arteries run in the outer (periosteal) layer of the dura mater, accompanied by one or two venous vessels. In the human dura, arterial branches form arterio-venous shunts and supply a rich capillary network of the inner (arachnoid-near) layer (Kerber and Newton, 1973; Roland et al., 1987). The remarkable dense vascularization of the dura mater is in contrast to the light red color of meningeal veins, suggesting very low oxygen consumption that leaves other functional interpretations, such as thermoregulation, open (Zenker and Kubik, 1996; Cabanac and Brinnel, 1985).

The meningeal innervation has been studied extensively in rodents, but there is general agreement that the findings conform, in principle, with the human meningeal system. The dura mater is innervated by bundles consisting of unmyelinated and myelinated nerve fibers (Andres et al., 1987), with diameters ranging from 0.1–0.4 µm (unmyelinated) and from 1–6 µm (myelinated including myelin sheath) in rat (Schueler et al., 2014).

Immunohistochemical observations indicate that most of the nerve bundles consist of mixed afferent and autonomic fibers, which split up into smaller branches and, finally, into single fibers. Trigeminal fibers, which originate in the ipsilateral trigeminal ganglion, and sympathetic fibers, predominantly arising from the ipsilateral superior cervical ganglion, form dense plexus around the middle, anterior and posterior meningeal artery, suggesting a vasomotor function (Keller and Marfurt, 1991; Mayberg et al., 1984; Uddman et al., 1989). An especially dense network of nerve fibers is found around dural sinuses (Andres et al., 1987). In addition, a prominent system of cholinergic nerve fibers originating from the otic and sphenopalatine ganglia surrounds mainly large meningeal blood vessels (Amenta et al., 1980; Edvinsson and Uddman, 1981; Artico and Cavallotti, 2001).

Ultrastructural analyses of trigeminal fibers reveal the typical details of non-corpuscular sensory endings, which can be extensively ramified, forming short bud-like extensions or longer branches at the vessel wall, but also within the connective tissue between blood vessels (Messlinger et al., 1993). In addition, at sites where the cerebral (bridging) veins enter the sagittal superior sinus, non-encapsulated Ruffini-like receptor endings have been described (Andres et al., 1987). Particular features of the sensory endings (von Düring et al., 1990) are the free areas not covered by Schwann cells, and the equipment with vesicles and a specific fibrous plasma (“receptor matrix”) accumulating adjacent to the cell membrane of the free areas (Andres et al., 1987).

Functionally, the trigeminal and the parasympathetic fibers mediate arterial vasodilatation, and the postganglionic sympathetic nerve fibers mediate vasoconstriction (Jansen et al., 1992; Faraci et al., 1989). The vasodilatation of meningeal arteries induced by cortical spreading depression in rat was abolished after sphenopalatine ganglionectomy (Bolay et al., 2002). There are multiple functional measurements of the meningeal vasoregulation, employing video microscopy and laser Doppler flowmetry, which all indicate regulation of meningeal arteries but obviously no venous vasoregulation (Gupta et al., 2006; Kurosawa et al., 1995; Fischer et al., 2010; Williamson et al., 1997).

The arterial vessels are accompanied by mast cells, arranged in a street-like manner frequently close to nerve fiber bundles, suggesting signaling functions (Dimlich et al., 1991; Dimitriadou et al., 1997; Keller et al., 1991). In addition, extensive networks of dendritic cells with access to the cerebrospinal fluid and resident macrophages exist in all meningeal layers, suggesting competent immune functions within these tissue (McMenamin, 1999; McMenamin et al., 2003).

1.1.2 Extracranial extensions of the meningeal innervation

Postmortem tracings with DiI show two systems of trigeminal fibers transversing the rat dura mater of the middle cranial fossa in a roughly orthogonal direction, one accompanying the middle meningeal artery (MMA), and the other running from the transverse sinus across the artery in a rostromedial direction (Strassman et al., 2004). Recent neuronal tracing (Schueler et al., 2014) has revealed that the MMA accompanying fiber plexus is formed by the spinosus nerve originating in the mandibular division (V3) of the trigeminal ganglion, while the MMA crossing plexus arises from the tentorius nerve originating in the ophthalmic division (V1). This innervation pattern conforms to the historical observations on the human meningeal system described by Luschka and Wolff's group (Luschka, 1856; Ray and Wolff, 1940).

Previous retrograde tracing studies in cat and monkey aimed at the question of whether intracranial structures may be innervated by divergent axon collaterals that also supply facial skin to explain pain referred to the surface of the head (Borges and Moskowitz, 1983; McMahon et al., 1985), but these studies brought no evidence for this hypothesis. Recently, however, it became clear that the rodent meningeal nerve fibers may traverse the cranium, and may communicate with extracranial structures such as the galea aponeurotica (Kosaras et al., 2009). Postmortem anterogradely traced meningeal nerve fibers in rat and human preparations were found to split up in several branches, some of which pass through sutures and along emissary veins and innervate the periosteum and deep layers of pericranial muscles (Schueler et al., 2014). In vivo retrograde tracing has confirmed this, and functional measurements have showed that at least some of the nerve fibers innervating pericranial muscles are collaterals of meningeal afferents innervating the dura mater (Schueler et al., 2013; Zhao and Levy, 2014).

1.1.3 Neuropeptides and their receptors in meningeal tissues

Immunohistochemical studies have identified various neuropeptides in nerve fibers innervating the dura mater (O'Connor and van der Kooy, 1986; von Düring et al., 1990; Keller and Marfurt, 1991; Messlinger et al., 1993) and blood vessels of the pia mater in different species, including humans (Edvinsson et al., 1988; You et al., 1995). The peptidergic nerve fibers form a dense network around blood vessels, but can also be found in non-vascular regions of the dura mater (Messlinger et al., 1993; Strassman et al., 2004). Meningeal nerve fibers immunoreactive for calcitonin gene-related peptide (CGRP), su...

Table of contents

• Cover
• Title Page
• Copyright
• Dedication
• Table of Contents
• List of Contributors
• Foreword
• Part I: Anatomy and physiology
• Part II: Special features of migraine pain
• Part III: Clinical characteristics of migraine
• Part IV: Migraine genetics and CSD
• Part V: Modeling and imaging inmigraine
• Index
• End User License Agreement