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Keywords:

  • migraine triggers;
  • headache;
  • meningeal nociceptors

Abstract

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

A number of distinct endogenous and exogenous factors have been implicated in migraine precipitation but the exact nature of the triggering process itself and its relationship to the genesis of the headache remains largely speculative. In this article, we examine the potential sites and downstream cascades through which migraine triggers might exert their action to promote the activation of the migraine pain pathway. We further look at the laterality of the headache as a potential indicator for the site of migraine pain initiation and examine the question of triggering factor specificity in relation to the current understanding of migraine pathophysiology.

There is a considerable amount of clinical data to suggest that most migraine attacks, despite their seemingly spontaneous nature, are triggered by a variety of endogenous and exogenous factors.1,2 Although a number of hypotheses of migraine origin have been set forth, the links between triggering factors and the migraine pain pathway remain largely understudied and therefore poorly understood. In the following paragraphs, we will critically discuss the potential sites, pathways, and downstream mechanisms through which migraine triggers might exert their action.

“TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

Despite the constant debate of whether migraine has a vascular, neuronal, or neurovascular origin, the headache itself is believed to arise as a result of the activation of a neuronal pathway comprised of peripheral cephalic trigeminal nociceptive neurons that innervate the intracranial meninges and their related large blood vessels (ie, meningeal nociceptors) and central neurons (dorsal horn, thalamic and cortical) that further process and transmit the peripheral nociceptive input.3 Neuronal signals ascending through the central part of the migraine pain pathway are believed to be further modulated, similar to nociceptive information arising from other tissues, by descending pathways that converge in the periaqueductal gray (PAG).4,5 These descending pathways, which project through the rostroventral medulla (RVM), are capable of promoting both inhibition and facilitation of ascending nociceptive information by modulating the activity of dorsal horn neurons that process and relay peripheral nociceptive input.6,7

In theory, a given triggering factor could provoke migraine pain by influencing directly or indirectly neurons at any given site (peripheral or central) along the ascending or descending nociceptive pathways. However, current understanding of pain neurobiology points to an obligatory role for nociceptor activation in the genesis of any acute and localized pain sensation. Yet, one migraine hypothesis contradicts this notion. According to this view, migraine headache, unlike any other known types of pain, can be triggered in the absence of nociceptor activation, simply as a consequence of a dysfunctional modulatory pathway: one that originates in the PAG. This view is based on a number of clinical observations. These include the emergence of headaches in a small number of nonmigraineurs implanted with electrodes at (or near) the PAG for relieving chronic pain,8,9 the presence of neurochemical abnormalities within the PAG of migraine patients,10 and the finding of activation during migraine attacks of a brainstem region that includes the dorsal raphe nucleus,11 which plays a role in pain modulation. Two main lines of evidence, however, cast considerable doubt on the role of the PAG and its related pain modulatory circuit as the “headache generating site” or “migraine-triggering zone.” The first is the finding that activation of descending pathways that project from the PAG to the RVM cannot initiate neuronal firing in previously silent nociceptive dorsal horn neurons (the ascending pathway). It should be pointed out, however, that neuronal perturbations at the PAG level (whether arising endogenously or triggered exogenously) can give rise to an increase in the firing rate of peripherally activated dorsal horn neurons,5,7 a mechanism that could enhance (but never trigger) migraine pain. The second argument against the PAG as the headache triggering zone is based on anatomical findings showing that descending modulatory pathways that arise in the PAG project via the RVM onto multiple segments of the spinal cord where they terminate on dorsal horn neurons.12,13 These anatomical findings strongly suggest that a dysfunctional PAG per se is unlikely to contribute to the generation of a distinct cephalic throbbing pain, such as that during a migraine attack, although it might play a role in promoting a general increase in pain sensitivity over multiple anatomical segments.

MIGRAINE TRIGGERING CASCADES

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

The notion that the genesis of acute migraine pain requires activation of meningeal nociceptors suggests that a given triggering factor is likely to exert a powerful modulatory effect on these sensory neurons either directly or indirectly. The diversity of factors capable of triggering migraine (stress, lack of sleep, changes in the levels of ovarian hormones, dietary products, environmental changes, etc) suggests 2 possible modes of action. In the first, various triggering factors converge on a single biological process that promotes the activation of meningeal nociceptors (eg, inflammation). In the second mode, different factors promote the activation of distinct pathways, all of which are capable of eliciting the activation of meningeal nociceptors.

Despite having now a better understanding of the basic response properties of meningeal nociceptors,14 how these neurons become activated during a migraine attack remains largely speculative. Electrophysiological studies of the sensory innervation of other tissues suggest that persistent activation of nociceptors as well as increases in their sensitivity to mechanical and thermal stimuli is often linked to a local inflammatory process affecting the neurons' receptive field. In the case of acute migraine attacks, despite the lack of direct evidence of local meningeal inflammation, a number of clinical and preclinical findings suggest that migraine is an inflammatory disorder. For example, during a migraine attack, intracranial levels of pro-inflammatory molecules such as calcitonin gene-related peptide (CGRP) and tumor necrosis factor are elevated.15,16 The intensification of the headache during physical activities associated with increased intracranial pressure (eg, straining, coughing, and bending over) provides a further indication of a process that likely involves an inflammatory-mediated hypersensitivity (sensitization) of meningeal nociceptors.17,18 Furthermore, there is abundant evidence for therapeutic efficacy of nonsteroidal anti-inflammatory drugs for acute migraine attacks.19 Finally, recent preclinical data indicate that that infusion of nitroglycerin, which is considered one of the most reliable triggers of migraine (as well as other primary headaches), promotes a delayed meningeal inflammation with a similar latency as the headache itself.20 Whether local meningeal inflammation is solely responsible for the persistent activation and sensitization of meningeal nociceptive neurons during a migraine attack remains to be determined.

Visual and other sensory auras precede the headache in about one-fifth of all migraineurs and the presence of other premonitory symptoms such as fatigue is reported in about one-third of patients. These findings suggest that certain cortical or subcortical brain regions serve as key integrating regions at which various endogenous and exogenous triggering factors act to promulgate a process (or processes) that activate meningeal nociceptors. While the integrating role of the cortex may be assumed for both migraine with aura and migraine without aura, in the specific case of migraine with aura it has been suggested that one or more genetic mutations render the cortex of these migraineurs hyperexcitable, with enhanced susceptibility to becoming affected by a variety of triggering factors.21 This theory further maintains that the effect of those triggering factors on the vulnerable cortex results in enhanced responsiveness manifested as a depolarizing electrical and metabolic events resembling the cortical spreading depression (CSD) of Leão. This cortical event is now believed to be the underlying mechanism of the migraine aura. The premise that a genetically modified, hyperexcitable cortex plays a role in promoting a CSD-like event in migraineurs has gained support recently from a study showing that mice bearing a genetic mutation responsible for a rare type of migraine known as familial hemiplegic migraine have a much reduced threshold for the initiation of CSD.22 Given that the migraine aura is often (but not always) followed by the headache, the process of CSD itself has been proposed to serve also as the mechanism responsible for the initial activation of the migraine pain pathway. The underlying mechanism has been suggested to involve a local release of mediators capable of activating meningeal nociceptors followed by a local meningeal neurogenic inflammation that further enhances and prolongs the nociceptors' activity and sensitivity.23

Although the CSD hypothesis of migraine remains one of the most tenable ones, the putative relationship between the various migraine triggers, a genetically modified hyperexcitable cortex, the emergence of CSD and the ensuing headache requires a careful examination. The first argument against the role of CSD in the triggering of migraine pain is a lack of evidence supporting the view that common migraine triggers (ie, stress, fatigue, hunger, estrogen withdrawal) are capable of directly promoting CSD or increasing the propensity to develop one. It should be emphasized, however, that there are 2 reported clinical cases in which relatively infrequent triggering events, including intense visual stimuli and vigorous physical activity, were able to provoke in few migraine patients changes in cortical activity24 resembling CSD, or spreading alterations in cerebral blood flow25 that coincided with the aura and were followed by a migraine-like headache. A second argument is that despite the current view that migraine is a channelopathy, there is currently only circumstantial evidence to suggest that migraine patients harbor one or more specific genetic mutations resembling those linked to familial hemiplegic migraine and that might render their cortex hyperexcitable.26 Furthermore, the current mechanistic view linking the CSD to a genetically modified (hyperexcitable) cortex cannot explain the laterality of these neurovascular phenomena in the face of one or more genetic mutations that lack regional specificity within the central nervous system, let alone confined to a single side of the cortex. Finally, while the question of CSD as the trigger of migraine pain remains intriguing, critically lacking in this hypothesis is evidence for a direct link between the CSD itself, its vascular manifestation and the activation of the meningeal sensory innervation.27

An additional, relatively newer hypothesis suggests that common migraine triggers such as stress, skipping a meal, and fatigue promote the headache through the activation of distinct but converging neuronal pathways that are not necessarily linked to CSD or aura. According to this view,28 these putative neuronal pathways originate in several brain nuclei that respond to the most common migraine triggers. These include the lateral hypothalamus and perifornical areas that become activated during food and sleep deprivation, and the bed nucleus of stria terminalis and paraventricular hypothalamic nucleus that are involved in regulating stress response. The neuronal outputs from these nuclei converge onto the superior salivatory nucleus (SSN), which further projects to the parasympathetic sphenopalatine ganglion (SPG). According to this hypothesis, indirect activation of the SPG by triggering factors (by way of the SSN) results in local meningeal release of parasympathetic-driven vasoactive and algesic mediators such as nitric oxide and acetylcholine that in turn are capable of enhancing directly or indirectly the responsiveness of meningeal nociceptors. The involvement of the parasympathetic trigeminal innervation in the triggering of migraine pain has largely been based on 2 main findings: the presence of enhanced parasympathetic tone during a migraine attack as indicated by nasal congestion, teary eyes and lacrimation, and the acute relief of migraine pain following administration of lidocaine in the vicinity of the SPG.29,30 It should be emphasized, nevertheless, that the emergence of parasympathetic-related symptoms coinciding with the head pain does not necessarily reflect activation of the SSN as these symptoms may also be promoted through the activation of a trigemino-parasympathetic reflex.31,32 The validity of the SSN-SPG pathway as a migraine triggering cascade therefore requires direct evidence showing the ability of migraine triggers to activate the SSN and SPG as well as the modulation of meningeal nociceptors' responsiveness by upstream activation of these nuclei.

In contrast to the above-mentioned neurogenic theories of migraine where cortical or subcortical areas are proposed as the sites at which migraine triggers exert their action, the vasogenic theory of migraine implicates a peripheral triggering site, in particular one that involves the intracranial vasculature and its related sensory innervation. The findings that a number of vasodilating agents including histamine, alcohol, nitroglycerin, and recently CGRP33 can trigger migraine (or migraine-like) headaches had contributed to the concept that meningeal and cerebral vasodilatation serves as a key triggering event in the genesis of migraine headache. However, numerous studies have yielded overwhelming evidence against this concept by showing a lack of correlation between vasodilatation and the headache34-37 as well as between vasodilatation and the activation of meningeal nociceptors.38 Despite the considerable evidence against intracranial vasodilatation as the triggering mechanism of migraine headache, the possibility of a distinct nonvasodilatory peripheral headache generator cannot yet be fully discounted. According to such an “alternative” peripheral mechanism, a given triggering factor might activate the migraine pain pathway by acting locally within the intracranial meningeal milieu. These factors might affect meningeal nociceptors directly or indirectly by acting on other meningeal constituents. For example, factors capable of interacting with meningeal vascular cells or local immune cells could potentially promote local release of mediators capable of activating meningeal nociceptors. Of particular interest is the potential ability of a number of triggering factors like stress, ovarian hormones, and dietary ingredients to promote the release of inflammatory mediators from resident meningeal mast cells39 and the ability of such mast cell-related agents to promote persistent activation of meningeal nociceptors and the migraine pain pathway.18,40

The notion that migraine triggers act in the periphery suggests that migraine attacks associated with such a mechanism are less likely to be associated with central nervous system (CNS)-related premonitory symptoms or aura. Given the paucity of studies examining the link between specific triggers and the presence of such premonitory symptoms, the existence of such “peripherally acting” triggering factors remains open to question. Nevertheless, one must also consider the possibility that some triggering factors promote the premonitory symptoms as well as the headache but rather through the activation of distinct pathways, especially given the varying latencies of the two. The finding that infusion of the migraine trigger nitroglycerin is associated in some patients with CNS-related premonitory symptoms41 while the headache itself might be attributed to a peripheral mechanism (ie, delayed meningeal inflammation)20 supports the notion of such distinct pathways.

MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

Although it is generally believed that migraine is a unilateral phenomenon, about 40% of migraineurs perceive the headache bilaterally.42 The exact mechanism accounting for the pattern of pain lateralization remains unknown, although the current view of migraine pathophysiology points to a unilateral CSD as the chief mechanism underlying one-sided migraine headaches. This is mainly because unilateral headaches are usually localized to the side on which vascular changes are observed (changes in cerebral blood flow) and from which the aura symptoms originate.43 Migraine with aura, of which CSD is currently considered the underlying mechanism, occurs, however, only in about 20% of migraineurs, far less then the percentage of individuals suffering from a unilateral headache (∼60%). Such inconsistency, nevertheless, may be resolved if one also considers “silent” cases of CSD as a mechanism underlying the remaining unilateral migraine episodes. The potential link between CSD and the emergence of a unilateral headache suggests that bilateral headaches might be promoted by different triggering factors as well as through a distinct mechanism of action. One potential candidate underlying bilateral headaches might involve a parasympathetic-related mechanism as suggested by a particular enhanced cranial parasympathetic response in bilateral migraineurs.44 A peripheral (ie, meningeal) triggering site is also a likely candidate. This is mainly because meningeal nociceptors as well as immune and vascular cells are unlikely to have lateral differences, for example in their response properties that could explain a distinct unilateral activation. Additional clinical studies are required to examine the potential links between specific triggering factors, premonitory symptoms and the presence of unilateral or bilateral headache. Further studies may also be able to explore the possibility that the site of migraine triggering itself plays only a minor role in promoting the lateralization while perturbation of modulatory pain pathways, such as those originating in the PAG, plays a larger or potentially key role.45

ARE MIGRAINE TRIGGERS SPECIFIC?

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

The most common factors implicated in migraine triggering are often very effective in precipitating other primary headaches. For example, factors such as stress, fatigue, not eating on time and changes in ovarian hormones almost equally precipitate tension-type headaches.1 Other factors such as changes in weather patterns and nitroglycerin infusion also seem to lack specificity for migraine.46-48 These clinical observations argue in favor of a rather generic mechanism that link these common factors with the mechanism that promotes headache. Given that most of these common triggers can be linked to unbalanced homeostasis (ie, stress, fatigue, hunger), it can be argued that the emergence of the head pain itself serves as a normal “built-in” physiological response that signals the presence of such homeostatic change. According to this view, it can be further speculated that individuals suffering from more frequent and disabling headaches are likely to have one or more additional susceptibilities that result in a lower threshold level for sensing these changes in homeostasis as well as an enhanced consequential activation of one or more trigeminal pain pathways that promote headache. Arguing against such generic headache generating mechanism are the unique characteristics of migraine (eg, throbbing pain, nausea, vomiting and photophobia). Whether these characteristics depend on a distinct peripheral origin (intracranial vs extracranial, vascular vs musculoskeletal) or the central neuronal pathway that relays and modulates the nociceptive information arising from these sites remains to be determined. One clue may by related to the occurrence of nausea, vomiting and photophobia also during meningitis-related headache,49 suggesting that migraine pain is likely mediated by a distinct neuronal pathway that is especially equipped to detect intracranial meningeal inflammation.

CONCLUDING REMARKS

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References

Current theories of migraine triggering sites and cascades remain speculative with little direct evidence to support any of them. This lack of information requires much additional preclinical work to examine how factors implicated in migraine triggering interact with the migraine pain pathway as well as other nonneuronal constituents that might play a role in promoting its activation. The multitude of triggering factors and the various “flavors” of migraines also calls for much needed clinical work to further examine the link between migraine triggers and the presence of premonitory symptoms, the unilaterally of the pain and potentially the existence of various biological markers. Findings from these studies will be instrumental in providing a better understanding of the underlying triggering cascades which will lead to development of evidence-based prophylactic treatments.

References

  1. Top of page
  2. Abstract
  3. “TRIGGERING POINTS” ALONG THE MIGRAINE PAIN PATHWAY
  4. MIGRAINE TRIGGERING CASCADES
  5. MIGRAINE TRIGGERING SITE AND HEADACHE LATERALIZATION
  6. ARE MIGRAINE TRIGGERS SPECIFIC?
  7. CONCLUDING REMARKS
  8. References