Chapter Eighteen - Meningeal Afferent Signaling and the Pathophysiology of Migraine

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Abstract

Migraine is the most common neurological disorder. Attacks are complex and consist of multiple phases but are most commonly characterized by intense, unilateral, throbbing headache. The pathophysiology contributing to migraine is poorly understood and the disorder is not well managed with currently available therapeutics, often rendering patients disabled during attacks. The mechanisms most likely to contribute to the pain phase of migraine require activation of trigeminal afferent signaling from the cranial meninges and subsequent relay of nociceptive information into the central nervous system in a region of the dorsal brainstem known as the trigeminal nucleus caudalis. Events leading to activation of meningeal afferents are unclear, but nerve endings within this tissue are mechanosensitive and also express a variety of ion channels including acid-sensing ion channels and transient receptor-potential channels. These properties may provide clues into the pathophysiology of migraine by suggesting that decreased extracellular pH and environmental irritant exposure in the meninges contributes to headache. Neuroplasticity is also likely to play a role in migraine given that attacks are triggered by routine events that are typically nonnoxious in healthy patients and clear evidence of sensitization occurs during an attack. Where and how plasticity develops is also not clear but may include events directly on the afferents and/or within the TNC. Among the mediators potentially contributing to plasticity, calcitonin gene-related peptide has received the most attention within the migraine field but other mechanisms may also contribute. Ultimately, greater understanding of the molecules and mechanisms contributing to migraine will undoubtedly lead to better therapeutics and relief for the large number of patients across the globe who suffer from this highly disabling neurological disorder.

Introduction

Migraine is a subtype of headache characterized by repetitive episodes of intense unilateral throbbing head pain lasting many hours to days. However, it is a multiphasic disorder that comprises complex symptomology that can vary greatly among patients. These complex features of migraine differentiate it from other types of chronic pain and include the presence of premonitory symptoms, an aura, and during the headache phase, severe nausea, vomiting, and hypersensitivity to light and sound. Although migraine is episodic in nature, together these collections of symptoms cause an entire attack to last close to a week, and given the severity, migraine has a significant negative impact on a patient's quality of life. The World Health Organization's Global Burden of Disease Study conducted in 2010 found migraine headache to be the third most prevalent disease across the globe, preceded only by dental caries and tension type headache.1 Given the current understanding of migraine as a pathological condition of the nervous system, migraine is thus the most common neurological disorder with an estimated 33% of women and 10% of men affected by the condition.1, 2, 3 Despite the prevalence, the basic physiology and underlying contributing factors to the development of migraine headache is still poorly understood.

Section snippets

Features of Migraine

Migraines comprise four phases: premonitory phase (also commonly referred to as the prodrome), aura, headache, and postdrome2, 3 (Fig. 1). Studies have estimated that the number of patients with migraine who experience premonitory symptoms may range from as low as 37% to as high as 80%.4, 5 The premonitory phase occurs hours to days before the actual headache and can be a reliable predictor of an upcoming migraine for some patients.4 This phase consists of symptoms that range in severity such

Current Migraine Treatments

Migraine is an extremely disabling disorder,1 a fact made more troubling by the lack of efficacy of currently available therapeutics. Treatment typically falls in one of the two categories, abortive and prophylactic. Abortive agents are taken at the onset of headache or during aura with the goal being termination or at least a decrease in intensity of the building attack. Prophylactic therapies are given daily to patients who have frequent migraines (e.g., > 5 per month) with the goal of

Anatomy of the Meningeal Afferent System

The meninges are innervated predominantly by afferents whose cell bodies reside in the trigeminal ganglion (Fig. 2). The trigeminal nerve is the fifth cranial nerve that exits the brainstem at the level of the pons as a single nerve root, passes through the trigeminal ganglion, and continues distally from the ganglion as separate nerve branches.28, 29 There are three major branches that emerge from the ganglion into V1, V2, and V3 subdivisions. Each branch innervates a distinct dermatome. The

Migraine Pathophysiology

Although the brain lacks sensory innervation, which renders it incapable of sensing noxious stimuli, studies dating as far back as 1940 have shown that sensory afferents that innervate the cranial meninges, particularly the dura mater, are in fact mechanically (and chemically) sensitive.32, 33, 34, 35, 36, 37, 38 The earliest of these studies showed that in response to stimulation of the meninges, conscious humans report pain and no other sensation, indicating that the meninges are innervated

Potential Mechanisms of Dural Afferent Activation

Dural afferents are capable of sensing noxious stimuli generated within the dura and the pain that arises during migraine is likely to involve the activation of these primary afferent nociceptors.55, 56 However, the events that lead to the activation and/or sensitization of these neurons are not fully known.8, 57, 58 The dura is often overlooked as just one of the three meningeal layers; however, the dura mater regulates events in the overlying skull during development. Ultimately, the dura

Ion Channels and Dural Afferent Activation

Acid-sensing ion channels or ASICs are a family of four ion channels consisting of, ASIC1–ASIC4, with several splice variants.75, 76, 77 ASIC1–3 are sensitive to various ranges of pH from approximately 4.5 to just above 7.0. ASIC4 is not a pH-sensitive channel. Although ASICs are abundant throughout the nervous system, including expression primary sensory neurons, ASIC3 is largely restricted to the periphery.77, 78 ASICs on dural afferents may act as an indicator of changes in extracellular pH.

Dural Afferent Input May Lead to Neuroplasticity

Although the events that actually initiate a migraine attack remain unknown, the ultimate activation of the trigeminovascular system is considered to be essential147, 148. Trigeminovascular activation may provoke release of multiple excitatory neurotransmitters including substance P, neurokinin A, and CGRP from dural afferent terminals resulting in neurogenic vasodilation of dural blood vessels, release of proinflammatory mediators, degranulation of mast cells, and plasma protein extravasation.9

Neuroplasticity and Migraine

As discussed above, there are a number of proposed mechanisms that may contribute to the pathophysiology of migraine, one of which involves “neuroplasticity” in the peripheral and central nervous systems. There are two different kinds of neuroplasticity, one that is beneficial, contributing processes within the brain that lead to learning and memory, and one that is harmful, contributing to pathological pain or migraine. The underlying mechanisms mediating these forms of plasticity are thought

CGRP and Migraine Plasticity

Numerous studies show that CGRP plays a critical role in migraine headache. CGRP is a neuropeptide produced by peripheral neurons commonly affiliated with nociceptive signals entering the spinal cord due to its release from C-fibers at this site.32, 34, 36 The role of CGRP in migraine is still evolving, but many advances have been made recently. As described above, it was previously hypothesized that the cause of migraine pain was due to vasodilation of blood vessels innervating the cerebrum39,

BDNF and Migraine

Long-term potentiation (LTP) is an example of neuroplasticity, where the persistent activation of a synapse leads to long-lasting changes in transmission between two neurons. While LTP has long been implicated in learning and the formation of memories at central synapses in the cortex and hippocampus, LTP can play an important role in the dorsal horn of the spinal cord leading to pain plasticity.91 LTP is separated into two phases: an early and late or maintenance phase. While early-phase LTP

Conclusion

Migraine is the most common neurological disorder and is one of the most disabling disorders worldwide. Surprisingly, the pathophysiological mechanisms contributing to this prevalent disorder remain poorly understood. One primary result of the poor understanding of the condition is slow development of novel therapeutics. The gold standard in the treatment of migraine, triptans, was developed on an outdated hypothesis for the mechanism contributing to migraine, vasodilation. Although they have

Acknowledgments

This work was supported by funding from the National Institutes of Health (NS072204) and the Migraine Research Foundation.

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