THE JOURNAL OF COMPARATIVE NEUROLOGY 493:9 –14 (2005)

Unitary Hypothesis for Multiple Triggers

of the Pain and Strain of Migraine
RAMI BURSTEIN* AND MOSHE JAKUBOWSKI
Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center;
Department of Neurobiology and the Program in Neuroscience, Harvard Medical School,
Boston, Massachusetts 02115

ABSTRACT
Migraine headache is triggered by and associated with a variety of hormonal, emotional,
nutritional, and physiological changes. The perception of migraine headache is formed when
nociceptive signals originating in the meninges are conveyed to the somatosensory cortex
through the trigeminal ganglion, medullary dorsal horn, and thalamus. Is there a common
descending pathway accounting for the activation of meningeal nociceptors by different
migraine triggers? We propose that different migraine triggers activate a wide variety of
brain areas that impinge on parasympathetic neurons innervating the meninges. According
to this hypothesis, migraine triggers such as perfume, stress, or awakening activate multiple
hypothalamic, limbic, and cortical areas, all of which contain neurons that project to the
preganglionic parasympathetic neurons in the superior salivatory nucleus (SSN). The SSN,
in turn, activates postganglionic parasympathetic neurons in the sphenopalatine ganglion,
resulting in vasodilation and local release of inflammatory molecules that activate meningeal
nociceptors. Are there ascending pathways through which the trigeminovascular system can
induce the wide variety of migraine symptoms? We propose that trigeminovascular projec-
tions from the medullary dorsal horn to selective areas in the midbrain, hypothalamus,
amygdala, and basal forebrain are functionally positioned to produce migraine symptoms
such as irritability, loss of appetite, fatigue, depression, or the quest for solitude. Bidirec-
tional trafficking by which the trigeminovascular system can activate the same brain areas
that have triggered its own activity in the first place provides an attractive network of
perpetual feedback that drives a migraine attack for many hours and even days. J. Comp.
Neurol. 493:9 –14, 2005. © 2005 Wiley-Liss, Inc.

Indexing terms: headache; PAG; nociception; trigeminal; stress; sleep; olfaction

ANATOMY OF THE PAIN spinal neurons. Whereas electrical brainstem stimulation

per se did not induce any activity in the spinal nociceptive
Migraine is a recurring neurological disorder commonly
neurons when they were quiet, it clearly increased or
described as unilateral throbbing headache, readily aggra-
vated by routine activities. The sensory discriminative decreased their response magnitude to noxious and innoc-
aspect of migraine pain is mediated by activation and uous stimulation of their cutaneous and visceral receptive
modulation of nociceptive trigeminothalamic tract neu- fields (Porreca et al., 2002).
rons by peripheral drivers and central modulators, respec- The initiation of migraine headache is commonly asso-
tively. In the case of the trigeminothalamic tract, the role ciated with a wide variety of circumstances, such as hor-
of driver is played by meningeal nociceptors, whereas
modulation is provided by inhibitory and facilitatory neu-
rons in the brainstem. Evidence for the driving role of
meningeal nociceptors comes from studies in which awake Grant sponsor: National Institutes of Health; Grant number: DE13347;
Grant number: NS051484; Grant number: NS35611 (to R.B.).
patients experienced headache in response to electrical
*Correspondence to: Rami Burstein, Department of Anesthesia and Crit-
stimulation of their dura (Penfield and McNaughton, ical Care, Harvard Institutes of Medicine, Room 830, 77 Avenue Louis
1940; Ray and Wolff, 1940). Evidence for descending mod- Pasteur, Boston, MA 02115. E-mail: [email protected]
ulation comes from studies that examined the effects of Received 27 April 2005; Accepted 3 June 2005
electrical stimulation of the periaqueductal gray (PAG) DOI 10.1002/cne.20688
and rostral ventromedial medulla (RVM) on nociceptive Published online in Wiley InterScience (www.interscience.wiley.com).

© 2005 WILEY-LISS, INC.

10 R. BURSTEIN AND M. JAKUBOWSKI

sensitive ion channel receptor (Waldmann et al., 1997).

Consequently, the activated meningeal nociceptors re-
lease calcitonin-gene-related peptide (Ebersberger et al.,
1999) from their peripheral branches, resulting in neuro-
genic inflammation in the dura (Goadsby and Edvinsson,
1993).
In contrast to the ongoing effort to understand how aura
triggers activity in meningeal nociceptors, little attention
was given to the mechanisms by which brain areas in-
volved in regulation of stress, menstrual cycle, sleep, food
intake, or responses to olfactory stimuli could activate
meningeal nociceptors and trigger the headache. Is there
a common pathway that activates meningeal nociceptors
for a variety of migraine triggers? We are proposing that
such a pathway involves pre- and postganglionic parasym-
pathetic neurons in the superior salivatory nucleus (SSN)
and sphenopalatine ganglion (SPG), respectively. Accord-
ing to our hypothesis, migraine triggers either activate or
originate in a number of brain areas whose projections
converge on the SSN. The SSN, in turn, stimulates the
release of acetyl choline, vasopressin intestinal peptide,
and nitric oxide from meningeal terminals of SPG neu-
rons, resulting (directly or indirectly) in a cascade of
Fig. 1. The trigeminovascular pathway subserving migraine pain. events that include the dilation of intracranial blood ves-
Neurons in the trigeminal ganglion (Tg) that innervate the meninges
(i.e., meningeal nociceptors) carry pain signals to trigeminovascular
sels, plasma protein extravasation, and local release of
neurons in the spinal trigeminal nucleus (SpV). From there the pain inflammatory molecules that activate adjacent terminals
signals are conveyed to several thalamic nuclei (Th) en route to the of meningeal nociceptors.
somatosensory cortex, where the perception of pain is formed. Several lines of evidence support this parasympathetic
hypothesis: 1) meningeal blood vessels are densely inner-
vated by parasympathetic fibers (Larsson et al., 1976;
Nozaki et al., 1993; Suzuki and Hardebo, 1993); 2) pregan-
monal milieu, periods of stress, poststress periods, skip- glionic parasympathetic neurons in the superior saliva-
ping a meal, lack of sleep, olfactory stimulation, and tory nucleus increase their activity after activation of
several types of aura (Liveing, 1873; Zagami and Rasmus- meningeal nociceptors (Knight et al., 2005); 3) ongoing
sen, 2000). These associations raise the possibility that a activity in meningeal nociceptors appears to depend on
migraine attack originates in brain areas that are not enhanced activity in the SPG (Bolay et al., 2002); 4) para-
directly involved in nociception, but are wired to activate sympathetic tone is enhanced during migraine, as evi-
the trigeminovascular pathway. The trigeminovascular denced by lacrimation, teary eyes, nasal congestion (Live-
pathway consists of first-order nociceptors in the trigem- ing, 1873); and 5) blockade of the sphenopalatine ganglion
inal ganglion that innervate the meninges; second-order provides partial or complete relief of migraine pain
trigeminothalamic tract neurons that receive sensory in- (Sluder, 1908; Dalessio, 1980; Kudrow, 1980; Diamond
puts from the meninges, periorbital skin and neck mus- and Dalessio, 1982; Waldman, 1990, 1993; Reutens et al.,
cles; third-order thalamocortical neurons that process in- 1991; Kudrow et al., 1995; Maizels et al., 1996; Yarnitsky
coming pain signals from the trigeminal nerve, including et al., 2003).
the meninges; and cortical neurons located in the first The SSN receives extensive input from more than 50
somatosensory cortex (Fig. 1). brain areas distributed throughout the forebrain, dien-
cephalon, midbrain, pons, and medulla (Spencer et al.,
ANATOMY OF THE STRAIN: ACTIVATION 1990). SSN-projecting neurons located in some of these
OF THE TRIGEMINOVASCULAR brain areas are theoretically positioned to mediate the
onset of a migraine by means of their involvement in
PATHWAY BY THE LIMBIC SYSTEM AND olfactory perception, physiological functions, emotional re-
HYPOTHALAMUS sponses, and hormonal secretions (Fig. 2A). The neuro-
The observation that visual aura precedes the onset of anatomy of a few examples is illustrated in Figure 2B. The
headache by several minutes promoted extensive research piriform cortex processes olfactory information (Wilson,
on the neural substrate by which cortical spreading de- 2001) and may therefore be positioned to mediate the
pression can result in activation of meningeal nociceptors. action of migraine-triggering odorants, such as perfume or
In the wake of cortical spreading depression, the blood– fried food. The lateral hypothalamus and perifornical area
brain barrier becomes more permeable (Moskowitz and contain hypocretinergic neurons that become active dur-
Cutrer, 1993; Gursoy-Ozdemir et al., 2004), allowing po- ing food deprivation (Qu et al., 1996; Sakurai et al., 1998;
tassium and hydrogen ions to diffuse from the surface of Elmquist et al., 1999; Diano et al., 2003) and sleep depri-
the cortex to the pia where they activate C-fiber menin- vation (Yoshida et al., 2001; Zeitzer et al., 2003); such
geal nociceptors (Moskowitz and Macfarlane, 1993). This hypocretinergic neurons may mediate the triggering of a
activation appears to involve direct depolarization by po- migraine attack when the patient skips a meal or when
tassium ions and action of hydrogen ions through the the patient is mildly sleep-deprived. The tuberomammil-
vallinoid receptor (Caterina et al., 1997) or the acid- ary nucleus (TMN) contains histaminergic neurons that
CNS ROOTS OF MIGRAINE 11

Fig. 2. A proposed parasympa-

thetic pathway for the activation of
meningeal nociceptors. Pregangli-
onic parasympathetic neurons in
the superior salivatory nucleus
(SSN) can trigger intracranial va-
sodilation and the release of nitric
oxide in the meninges through
postganglionic parasympathetic
neurons in the sphenopalatine
ganglion (SPG). A: The SSN re-
ceives input from over 50 limbic
and hypothalamic brain areas (red
dots) whose activity may be influ-
enced by common migraine trig-
gers. B: Examples of SSN afferents
proposed to be involved in mi-
graine triggering by olfactory stim-
uli (Pir), food and sleep depriva-
tion (LH), stress or poststress
(PVN, BNST, PAG). BNST, bed
nucleus stria terminalis; LH, lat-
eral hypothalamus; PAG, periaq-
ueductal gray; Pir, piriform cortex;
PVN, paraventricular hypotha-
lamic nucleus.

begin to fire at the end of the sleep period and have been graine must reach and alter the activity of hypothalamic
implicated in cortical arousal and the process of waking up and limbic structures that integrate sensory, physiologi-
(Schwartz et al., 1991; Lin et al., 1996; Steininger et al., cal, and cognitive signals that drive behavioral, affective,
1999); such arousal neurons may also be involved in the and autonomic responses. Brain areas involved in the
triggering of early-morning migraine. The bed nucleus of execution of such responses include the parabrachial com-
stria terminalis (BNST), the paraventricular hypotha- plex, PAG, hypothalamus, amygdala, septum, nucleus ac-
lamic nucleus (PVN), and the PAG are all involved in the cumbens, bed nucleus of the stria terminalis, and basal
circuitry that regulates “stress response.” BNST neurons, ganglia (Norgren, 1970; Panksepp, 1971; Kruk et al.,
which regulate the hypothalamic–pituitary–adrenal axis, 1983; Swanson, 1987; Lin et al., 1989; Bernardis and
appear to mediate long-lasting behavioral responses dur- Bellinger, 1993, 1998; Roeling et al., 1993; Scammell et
ing sustained stress, which persist long after the termina- al., 1993; Simerly, 1995; Saper, 1995; Sherin et al., 1996;
tion of stress (Walker et al., 2003; Forray and Gysling, Peyron et al., 1998). Many of these brain areas receive
2004); such neurons may be involved in stress-induced direct inputs from laminae I–II and V neurons located in
migraine and also in migraine triggered after the termi- the ventrolateral area of the upper cervical and medullary
nation of stress. Parvocellular PVN neurons that project dorsal horn (Fig. 3A)—an area containing the majority of
to sympathetic and parasympathetic preganglionic neu- second-order trigeminovascular neurons (Burstein and
rons in the brainstem and spinal cord promote the auto- Giesler, 1989; Burstein et al., 1990; Keay and Bandler,
nomic part of the stress response (Swanson and 1992; Burstein and Potrebic, 1993; Strassman et al., 1994;
Sawchenko, 1980; Coote, 2005), which includes localized Bernard et al., 1995; Bester et al., 1995; Vanderhorst et
cerebrovascular vasodilation in the early phase of the al., 1996; Malick and Burstein, 1998; Malick et al., 2000).
migraine attack (Olesen, 1998). Ventrolateral PAG neu- We propose that these ascending pathways are func-
rons involved in passive emotional coping with inescap- tionally positioned to produce irritability, loss of appetite,
able stressors such as repeated defeat in social encounters sleepiness, fatigue, chill, stress, depression, emotional
(Bandler et al., 2000; Keay and Bandler, 2001) may me- arousal, decreased motivation, the quest for solitude, and
diate the onset of increased migraine frequency associated lethargy during migraine (Fig. 3B). For example, loss of
with a long period of social stress such as divorce. appetite, sleepiness, and irritability during migraine may
be mediated by trigeminovascular projections to the lat-
ANATOMY OF THE STRAIN: ACTIVATION eral hypothalamus; in this area, neurons expressing
melanin-concentrating hormone or hypocretin regulate
OF THE HYPOTHALAMUS AND LIMBIC food and water intake, sleep, and arousal (Lin et al., 1989;
SYSTEM BY THE TRIGEMINOVASCULAR Peyron et al., 1998; Chemelli et al., 1999) through wide-
PATHWAY spread projections to the cerebral cortex, brainstem, and
The most frequently reported symptoms associated with spinal cord (Bittencourt et al., 1992; Bittencourt and
migraine are depression, stress, irritability, fatigue, sleep- Elias, 1993; Sakurai et al., 1998; van den Pol, 1999;
iness, exaggerated emotional responses, nausea, and loss Elmquist et al., 1999). Migraine-associated stress may be
of appetite. To elicit these symptoms, pain signals that mediated by trigeminovascular projections to the paraven-
originate in the trigeminovascular pathway during mi- tricular nucleus of the hypothalamus; this nucleus con-
12 R. BURSTEIN AND M. JAKUBOWSKI

Fig. 3. Proposed mechanism

for the initiation of symptoms com-
monly associated with migraine
headache by ascending trigemino-
vascular pathways to the brain-
stem, hypothalamus, and basal
ganglia. A: Trigeminovascular
neurons in the spinal trigeminal
nucleus (SpV) project to multiple
limbic and hypothalamic brain ar-
eas (red dots) whose activity may
underlie common migraine symp-
toms. B: Examples of SpV projec-
tions proposed to be involved in
stress (PVN), decreased motiva-
tional state (VP/SI), pursuit of sol-
itude (PAG), sleepiness, irritabil-
ity, and loss of appetite (LH). LH,
lateral hypothalamus; PAG, peri-
aqueductal gray; PVN, paraven-
tricular hypothalamic nucleus; VP/
SI, ventral pallidum/substantia
innominata.

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