The Mode of Action of Migraine Triggers: A Hypothesis

Abstract

Objectives.-To review conjectured modes of action of migraine triggers and to present a new hypothesis about them. Background.-Migraine attacks are initiated in many migraineurs by a variety of "triggers," although in some patients no external trigger can be identified. Many triggers provoke attacks with such a short latency that only some kind of neural mechanism can explain the triggering.Results.-We present here a hypothesis that the pain of migraine has its ultimate origin in the cortex, but that the immediate generator is in the brainstem. Our hypothesis is that most migraines have triggers that produce excitation of cortical neurons and that this directly causes withdrawal of descending sensory inhibition originating in the brainstem. A wide range of evidence from the literature that cortical activation induced by a number of different mechanisms often produces headache is presented to support this notion. Several nuclei in the brainstem appear to participate in the selective control of trigeminovascular sensation through descending inhibitory mechanisms that arise in the cortex. In this review we focus on 2 of them, the periaqueductal gray matter and nucleus raphe magnus. Our own past results and those of others show that this inhibition is specific for craniovascular sensation and involves the neurotransmitter 5-hydroxytryptamine. Finally, we summarize our own recent experiments, which show that cortical activation by migraine triggers (including cortical spreading depression) inhibits neuronal discharge in the brainstem and facilitates trigeminovascular sensation. Conclusion.-If the hypothesis can be proven and the neurotransmitters involved in the hypothetical trigger pathway can be identified, it may be possible to develop novel migraine preventative therapies.Key words: migraine, migraine trigger, cerebral cortex, brainstem, trigeminovascular sensory system Abbreviations: 5-HT 5-hydroxytryptamine, CGRP calcitonin gene-related peptide, CSD cortical spreading depression, DC direct current, ECT electroconvulsive therapy, LC locus coeruleus, NO nitric oxide, NRM nucleus raphe magnus, NTS nucleus tractus solitarius, PAG periaqueductal gray matter, PET positron emission tomography, SP substance P, TMS transcranial magnetic stimulation (Headache 2009;49:253-275) In this review, we present the hypothesis that most migraines have triggers that produce excitation of cortical neurons and that this excitation directly inhibits neurons in 2 brainstem nuclei: the periaqueductal gray matter (PAG) and the nucleus raphe magnus (NRM). These nuclei then release their ongoing descending control of dura mater sensation in the trigeminal nucleus and cause normal sensory traffic from the dura to be perceived as migraine pain.Migraine is one of our most common and debilitating organic diseases, yet bafflingly has no apparent pathology. It is a condition involving the "trigeminovascular system," in which the cranial vasculature, the trigeminal sensory system, and the central nervous system all play a part. Its cardinal fe...

Cortical spreading depression decreases Fos expression in rat periaqueductal gray matter

“…Our findings are in line with those of Lambert et al, [30] showing in cat CSDs or flashing light stimulation, both considered to be migraine triggers, reduce the inhibition of second order trigeminovascular neurons induced by PAG stimulation (unpublished results [30]), and inhibit neurons in nucleus raphe magnus [29].…”

“…It receives afferents from the cortex [46], where CSD occurs [19], and projects to hypothalamus [46], and raphe nuclei [5] thought to be involved in migraine pathogenesis. Neuronal dysfunction in the PAG may, thus, be involved in various features that accompany the migraine attack [30].…”

Migraine and motion sickness: What is the link?

“…Thus, it is not surprising that recent theories of migraine have focused on the brainstem as a source of the neurovascular disturbances and symptoms that accompany attacks (Lance and Goadsby, 2005;Lambert and Zagami, 2009). …”

Trigeminal Nociceptive Transmission in Migraineurs Predicts Migraine Attacks

“…From a pathophysiological point of view, migraine is understood as a paroxysmal CNS dysfunction. Neuronal circuits involved in migraine are of intense research interest (Lambert and Zagami, 2009). Although the pathophysiology of migraine is not yet fully understood, it has been postulated that peripheral events such as the activation of the trigeminovascular system lead to vasodilatation and plasma extravasation of meningeal vessels are most likely only a secondary event, as the origin of migraine attacks lies in the CNS (Goadsby, 2009).…”

“…Migraineurs are characterized by an alteration of the interictal cortical excitability level, pointing to a deficit of filter mechanisms that is believed to protect individuals against sensory overload (Aurora et al, 2007;Coppola et al, 2007). During the headache attack, the function of brainstem nuclei involved in endogenous pain control and pain transmission is thought to be altered (Afridi et al, 2005;Lambert and Zagami, 2009). Consequently, a dysfunction of peripheral and central parts of the trigeminovascular system is of specific interest (Borsook et al, 2006;DaSilva et al, 2007).…”