Headache ISSN 0017-8748C© 2006 by American Headache Society doi: 10.1111/j.1526-4610.2006.00485.xPublished by Blackwell Publishing

Emerging Neural Theories of MigrainePathogenesis

Mast Cell Involvement in the Pathophysiology of MigraineHeadache: A Hypothesis

Dan Levy, PhD; Rami Burstein, PhD; Andrew M. Strassman, PhD

Migraine attacks are triggered by a variety of conditions including endogenous and exogenous factors. Evidencesuggests that activation and sensitization of primary afferent meningeal nociceptive neurons, the peripheral armof the trigeminovascular system, constitutes one of the earliest events promoting the intracranial pain of migraine.However, the link between the varied triggering factors and activation of meningeal nociceptive neurons is not com-pletely understood. Local inflammation with release of mediators from local immune/inflammatory cells is thoughtto play a critical role in such neuronal response. Meningeal mast cells may play such a role by virtue of their proximityboth to meningeal blood vessels and nociceptive axons and their ability to release a host of proinflammatory/algesicmediators. This paper reviews data relevant to the hypothesis that mast cells, upon activation by migraine triggers,contribute to the genesis of migraine headache. Epidemiologic findings, clinical data, and observations on anatomi-cal and physiological characteristics of mast cells converge to suggest an important role of these immune cells in thepathogenesis of migraine. Migraine triggers might directly or indirectly promote mediator secretion from meningealmast cells, and thereby cause inflammation and activation of the trigeminovascular system. While consistent, theevidence supporting mast cell involvement in the genesis of migraine is largely circumstantial to date. Further studiesare needed to test directly the nature of mast cell involvement in the pathogenesis of migraine headache.

Key words: migraine, headache, mast cell, allergy, inflammation, trigeminal

(Headache 2006;46[Suppl 1]:S13-S18)

Migraine, a chronic disease afflicting a substan-

tial proportion of the population, is generally charac-

terized by severe, throbbing headache accompanied

by nausea and vomiting with enhanced sensitivity to

light, sound, and smells. It is widely accepted that the

intracranial throbbing pain of migraine is mediated

primarily by neuronal activity along the trigeminovas-

From the Department of Anesthesia and Critical Care, BethIsrael Deaconess Medical Center and Harvard Medical School,Boston, Massachusetts.

Address all correspondence to Dr. Dan Levy, Department ofAnesthesia and Critical Care, Headache Research Labora-tory, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur,Boston, MA 02115.

cular pathway. Activation and sensitization of primary

afferent nociceptive neurons that innervate the in-

tracranial meninges and their related blood vessels (ie,

meningeal nociceptors) is thought to be the first step

in driving this sensory nociceptive system to promote

the sensation of pain. While the exact mechanisms un-

derlying activation and sensitization of meningeal no-

ciceptors are not completely understood, local inflam-

mation and release of mediators are thought to play a

key role. Triggering mechanisms underlying these im-

mune and neuronal responses are currently unknown.

Migraine attacks are triggered by a variety of

conditions.1-3 Hypothesized endogenous triggers in-

clude abnormal cortical activity reflected in the phe-

nomenon of cortical spreading depression, which is a

S13

S14 June 2006

slowly propagating ionic disturbance within the cere-

bral cortex that has been implicated in the migraine

aura,4-6 hyperexcitability of the parasympathetic sys-

tem,7 release of hormones involved in the stress re-

sponse, and in female patients changes in the level of

sex hormones associated with the menstrual cycle. Ex-

ogenous triggers may include dietary elements such as

cheese, chocolate, coffee, wine, and changes in weather

patterns.

The notion that all of these seemingly unrelated

factors are linked to the emergence of the episodic

intracranial head pain of migraine raises the possibil-

ity of a single biological phenomenon that is impinged

upon by these various triggers and that plays a criti-

cal role in promoting meningeal inflammation and the

ensuing activation and sensitization of meningeal no-

ciceptors.

The emergence of a local inflammatory response

in the meninges is widely accepted as a potential

contributor to the activation and sensitization of

meningeal nociceptors during migraine.8 Activation of

resident immune cells such as macrophages and mast

cells, which are a prominent feature of the intracranial

meninges, is likely to serve as a critical step in promot-

ing the enhanced excitability of meningeal nociceptors.

Meningeal mast cells are of special interest by virtue

of their proximity to meningeal blood vessels and pain

fibers, their ability to release a host of pronociceptive

mediators, and their propensity to be activated by the

various migraine triggering phenomena.9

BIOLOGY OF MAST CELLSMast cells are ubiquitous immunocompetent cells

that participate in numerous physiological and patho-

physiological conditions. Mast cells originate in the

bone marrow and migrate into connective tissues and

mucosal surfaces, where they gain mature morphologic

and functional characteristics under the influence of

local microenvironmental factors.10 While mast cells

share many characteristics such as their prototypical

cytoplasmic granules, they differ in characteristics in-

cluding size, granule contents, and receptor expres-

sion.11

Although mostly known for their role in allergic

responses, mast cells are important cellular compo-

nents that mediate other immune responses. Activa-

tion of mast cells results in the release of granule-

associated mediators (ie, degranulation) including his-

tamine, serotonin, nerve growth factor, proinflamma-

tory cytokines such as TNF-α, IL-1, and IL-6, and

various proteases such as tryptase. In various acti-

vation modes, mast cells can also generate de novolipid-derived mediators, including leukotrienes and

prostanoids, and can synthesize nitric oxide. Histor-

ically, the primary cause of mast cell activation has

been considered to be the cross-linking of the high-

affinity IgE receptor (FcεRI) by IgE and multivalent

antigen—a process that culminates in the explosive

release of preformed mediators (ie, immunological

activation) to produce the typical anaphylactic aller-

gic responses. However, in recent years, non-antigenic

pathways of activation have also been implicated in

many pathologic conditions. For example, free im-

munoglobulin, hormones, various cytokines, and vanil-

loid compounds are known to promote mediator secre-

tion from mast cells. Polycationic compounds such as

the neuropeptide substance P and bradykinin are also

known to promote mast cell activation and degranula-

tion. It should be noted that such mode of activation is

mediated through a src-like cytosolic protein tyrosine

kinases; an identical biochemical pathway is activated

following the cross-linking of the high affinity IgE re-

ceptor on mast cells by antigen.12

NEUROIMMUNE INTERACTIONSINVOLVING MAST CELLS

A functional neuroimmune interaction involving

mast cells and nociceptive neurons is supported by (1)

the close proximity of mast cells to nociceptive nerve

endings in many cutaneous and deep tissues includ-

ing dermis, temporomandibular and knee joints, blad-

der, and meninges; (2) the activation of mast cells by

neuropeptide secreted from nociceptors (neurogenic

inflammation); (3) the secretion by mast cells of a mul-

titude of mediators capable of interacting with noci-

ceptors; and (4) their putative contribution to inflam-

matory chronic painful conditions such as interstitial

cystitis, irritable bowel syndrome, and arthritis.13-15

Based on their prominent location in the meninges

and their activation by a neurogenic, substance P-

dependent process,16-18 mast cells were also suggested

to play a possible role in migraine.9 Several lines of

Headache S15

evidence support the notion that mast cell activation

and mediator release promote neuronal changes re-

flecting neuronal hyperexcitability. For example, mast

cells were implicated in promoting enhanced excitabil-

ity of airways and the small intestine vagal afferent19,20

and enhanced neurotransmission in sympathetic gan-

glia.21 However, it is unclear whether mast cell acti-

vation, the ensuing release of mediators, and down-

stream events such as leukocyte recruitment or other

mast cells-related inflammatory responses can alter

the electrophysiological properties of nociceptors to

promote activation of nociceptive pathways.

CLINICAL EVIDENCE FOR MAST CELLINVOLVEMENT IN MIGRAINE

Allergic Diseases and Migraine.—Epidemio-

logical studies suggest an association between mi-

graine and mast cell-related diseases such as asthma

and allergies.22-24 In addition to data on comorbidi-

ties, compelling evidence suggests that maternal mi-

graine may be associated with an increased risk of mast

cell-related asthma and eczema in children,25 a finding

that further eludes to a possible genetic link between

mast cell-related diseases and migraine. The biologi-

cal mechanism underlying an association between mi-

graine and atopic diseases, however, has not been elu-

cidated to date.

Additional support for a possible involvement

of mast cell in migraine comes from clinical stud-

ies reporting migraine-like symptoms that are asso-

ciated with allergy season26 and allergic-related nasal

and ocular symptoms that frequently accompany mi-

graine.27-29 In fact, many self-diagnosed sinus-related

headaches appear to be rediagnosed as migraine.26

Other allergic-like symptoms, including nausea, vom-

iting, diarrhea, malaise, and fatigue also accompany

migraine attacks.30 Of particular interest is the phe-

nomenon of cyclic vomiting syndrome, a childhood

form of abdominal migraine that has been suggested

to be associated with changes in gastrointestinal dys-

motility and that can also be explained by allergic hy-

persensitivity.

That mast cells may play a role in migraine is

also consistent with data from studies of inflammatory

mediators. Increased levels of plasma histamine and

tryptase, both markers of mast cell activation, as well as

other mast cell mediators such as the cytokines TNF-α

and IL-1 have been observed in migraine.31-35 Further

support comes from another line of studies showing

that systemic administration of histamine can promote

migraine-like headache in susceptible individuals36,37

and that antihistaminergic agents may serve as pro-

phylactic migraine treatment.38

That certain foods, many of which cause allergic-

like symptoms in standard laboratory tests, are mi-

graine triggers for some patients is also consistent

with mast cell-mediated component of migraine.37,39-42

Across studies of varying quality, some of which were

placebo-controlled, 30% to 55% of migraine patients

experienced improvement in migraine by avoiding

specific foods.37,39-42 Although the nature of food-

induced migraine headache is not well understood,

the clinical evidence of effective prophylaxis using the

mast cell stabilizer cromolyn43-47 provides further sup-

port for a possible link between mast cells and mi-

graine.

Although migraine might share some of the bio-

logical underpinnings of mast cell-related symptoms, it

is clear that not all allergic reactions or asthma attacks

arising from antigen binding, IgE receptor cross link-

ing, and explosive mast cell degranulation culminate

in migraine headache. Whether elevated serum levels

of IgE found in migraine patients could alone play a

role in migraine even in the absence of antigen needs

to be further evaluated. One notion is that aggregation

of the Fc IgE receptor itself could lead at some point to

a preferential release of inflammatory mediators.48 In

addition, such aggregation may also render meningeal

mast cell more sensitive to other migraine triggering

factors (discussed below).

Nonimmunological Activation of Mast Cells inMigraine.—Although the nature of the relationships

among mast cells, allergies, and migraine is still a mat-

ter of debate, migraine was also linked to other nonal-

lergic conditions that involve mast cell activation. For

example, the incidence of migraine is increased in in-

terstitial cystitis and irritable bowel syndrome,9 both

of which involve “nonallergic” mast cell activation in

the absence of serum IgE elevations. Thus, it can be

argued that mast cells could play a role in migraine

pathophysiology by means of non-IgE-dependent

processes. One established migraine precipitator is

S16 June 2006

psychological stress, which has been shown to promote

activation of meningeal mast cells and local inflamma-

tory reaction,49 possibly through corticotropin releas-

ing hormone-related process.

Another migraine trigger that might be related

to mast cells is changes in ovarian sex hormone lev-

els associated with menstruation. Additional work by

Theoharides’ group has shown the presence of estro-

gen receptors on meningeal mast cells50 and the ability

of estrogen to influence meningeal mast cell secretion.

Whether such receptors play a role in promoting ac-

tivation of the trigeminovascular system warrants fur-

ther examination.

A dysfunctional parasympathetic system has been

suggested to play an important role in migraine.7

Migraine-related “allergic” symptoms such as lacrima-

tion and teary eyes were suggested to be related to an

enhanced parasympathetic tone. Although the mech-

anisms underlying such autonomic changes are not

well understood, a possible mechanism linking them

to cortical spreading depression has recently been sug-

gested.51 While mechanisms relating activation of the

parasympathetic system and the pain of migraine are

currently unknown, local meningeal interaction be-

tween parasympathetic neurons and mast cells may

play a role.52,53

Although the idea of mast cell involvement in mi-

graine, especially as an aspect of allergic disease, gener-

ated considerable excitement in the 1980s,54,55 medical

literature of the 1990s and this decade contains rela-

tively few references for mast cell contribution to mi-

graine. The apparent waning of interest in these ideas

might be attributed at least in part to the 1988 pub-

lication and subsequent widespread adoption of the

International Headache Society (IHS) diagnostic cri-

teria for headache. The IHS criteria compartmentalize

headache diagnoses into discrete, nonoverlapping en-

tities. For example, the criteria do not mention nasal

drainage or other similar symptoms as defining charac-

teristics of migraine but list purulent nasal discharge as

a defining characteristic of acute sinus headache.56,57

The wholesale adoption of the IHS diagnostic crite-

ria may have resulted in an exclusionary approach to

defining headache types that discouraged scientific in-

quiry into hypotheses such as that of the role of allergy

and mast cells in migraine pathophysiology.

CONCLUSIONSEpidemiologic data, clinical observations, and

anatomical and physiological characteristics of

meningeal mast cells converge to suggest an impor-

tant role of these immune/inflammatory cells in the

pathogenesis of migraine. Migraine triggers might

directly or indirectly activate meningeal mast cells,

which through release of inflammatory mediators

could cause activation of the trigeminovascular

system. While consistent, the evidence supporting this

hypothesis is largely circumstantial to date. Further

studies are needed to test directly the nature of mast

cell involvement in the pathogenesis of migraine.

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