ISSN 0017-8748

Headache doi: 10.1111/head.13081

C 2017 American Headache Society
V Published by Wiley Periodicals, Inc.

Supplement Article
The Trigeminovascular Pathway: Role of CGRP
and CGRP Receptors in Migraine
Lars Edvinsson, MD, PhD

The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP)
and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine
and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP
can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies
that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP
and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is
still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites,
peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This
review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in under-
standing the complexity of the trigeminovascular pathway and its peptide transmitters.

Key words: CGRP, CGRP receptor, CLR, RAMP1, gepants, monoclonal antibodies

(Headache 2017;57:47-55)

Primary headache and migraine in particular, is
among the top 10 most common causes of disability
in the world, posing a heavy burden on the individ-
ual and society.1 Promising results from experimen-
tal and clinical translational research are providing
a better understanding of the underlying neurobiol-
ogy of this disorder and options for improved
therapy.
Over the years, many neurotransmitters or neu-
romodulators have been considered to be involved
in migraine but none were shown to be a key play-
er. It now appears that the CGRP pathway plays a
From the Department of Medicine, Lund University, Lund,
Sweden.
Address all correspondence to L. Edvinsson, Professor,
Department of Medicine, University Hospital, 221 85 Lund,
Sweden.
dominant role in migraine; this was first suggested
in 19852 and subsequently verified by a series of cli-
nical translational studies.3-5 It is remarkable
that all of the clinical trials with anti-CGRP medi-
cations have been positive, whether in targeting
acute attacks, preventing attack onset, or reducing
attacks in chronic migraine or frequent episodic
migraine.6,7 In addition, these effects have been
achieved without significant adverse events. The
CGRP-related treatments do not cause vasocon-
striction, one of the major limitations in the use of
triptans. CGRP receptor antagonists, the gepants,
were shown some time ago to be effective in acute
migraine; however, their clinical development was
temporarily halted due to liver toxicity following
continuous exposure to the initial drugs. Currently,
ubrogepant, which is putatively without the toxicity
issue, is now in phase III trials. In addition to the

Conflict of Interest: The author declares no support from any

Accepted for publication March 7, 2017. organization for the submitted work.

47
48
gepants, a series of fully humanized monoclonal
antibodies against CGRP or the CGRP receptor
have been developed for prophylactic treatment of
chronic migraine (attacks >15 days/month) and for
frequent episodic migraine. The antibodies current-
ly in clinical trials are showing significant relief in
chronic and frequent episodic migraine with no
serious side effects.
The site of action of anti-migraine drugs has
been discussed for decades. Accumulating evidence
suggests migraine is initiated in subcortical brain
regions, as exemplified by premonitory studies8 and
continuous scanning of the migraine cycle.9 Current
work suggests that a putative driver of migraine
pathology lies in the hypothalamo-brainstem con-
nectivity, hypothalamic links with the spinal trigem-
inal nuclei to the trigeminovascular system, as well
as to the migraine generator in the dorsal rostral
pons.9,10 Identification of these key regions and
connections is intriguing, but still very little is
known about the underlying molecular mechanisms
in migraine. Imaging studies show activation of
regions that contain numerous neurons and nerve
fibers, with a vast array of neurotransmitters, con-
nected with billions of synapses and receptors. This
complexity underscores the difficulty in pinpointing
putative therapeutic targets within these regions.
CGRP does play a role in a number of the cen-
tral brain regions associated with migraine; howev-
er, it seems unlikely that these sites are the direct
targets of the effective CGRP therapies. Gepants
are small molecules with limited ability (2%) to
cross the bloodbrain barrier (BBB), and the anti-
bodies are much larger molecules (1500 times larg-
er) that are unable to pass the BBB (<0.01%), thus
effectively excluding them from having a major site
of action within the CNS. This suggests that the tar-
gets of the anti-migraine agents are located in areas
not limited by the BBB, such as intra- and extracra-
nial blood vessels, dural mast cells, and peripheral
parts of the trigeminal system.
In this article I will briefly touch on the history
behind the discovery of the role of CGRP in
migraine and discuss current aspects of the com-
plexity of the trigeminovascular pathway and the
messenger molecules involved.
May 2017
Innervation of Cranial Tissues Related to
Migraine.While the cranial autonomic and senso-
ry systems have been studied for decades, the sig-
nalling molecules involved were only known
indirectly. In the early studies, it was generally
assumed that each nerve cell synthetizes and
releases only one type of neurotransmitter, a
concept known as Dales principle.11 This was
exemplified by the sympathetic system with nor-
adrenaline and the parasympathetic nerves with
acetylcholine, both of which innervate the cerebral
arteries and other cranial structures. Demonstration
of vesicular noradrenaline in perivascular nerve
networks in cerebral arteries was first possible with
the Falck-Hillarp histofluorescence method,12 while
the parasympathetic nerves were identified using
indirect methods such as the acetylcholinesterase
staining method.13 These autonomic nerve fibers
showed close ultrastructural associations at the lev-
el of the perivascular nerve terminals and exhibited
functional interactions.14 The classical paradigm,
however, was challenged by findings that ATP and
adenosine also can be released with catechol-
amines, both in the periphery (adrenal medulla)
and in the brain.15 A paradigm shift occurred with
the development of immunohistochemical methods
that could be used to demonstrate neuropeptides.
In the cranial circulation, this was first exemplified
by the demonstration of vasoactive intestinal pep-
tide (VIP) in parasympathetic nerve fibers of the
cerebral circulation.16,17 Subsequently, several regu-
latory peptides were found co-localized with
classical neurotransmitters.18 The technological
advancements resulted in a decade of intense
research in which numerous neuropeptides were
demonstrated in various parts of the body. During
this period, our interest focused on the brain circu-
lation and the role of neuropeptides in particular.19
We developed methods to understand the role of
these peptides in regulation of the cerebral circula-
tion using combined anatomical, neurochemical,
and functional approaches. The autonomic and sen-
sory systems were soon found to contain numerous
neuronal messenger molecules, yet even now, their
functional significance is only partially understood
(Fig. 1).
Headache 49

Fig. 1.Schematic demonstration of the perivascular nerves in intracranial arteries. (i). The sympathetic fibers originate in the
superior cervical ganglion and store noradrenaline (NA), ATP, and neuropeptide Y (NPY). (ii). Parasympathetic nerves have
their origin mainly in the otic and sphenopalatine ganglia and store acetylcholine (ACh), vasoactive intestinal peptide (VIP),
peptide histidine isoleucine or methionine (PHI/PHM), pituitary adenylate cyclase activating peptide (PACAP), nitric oxide
synthase (NOS). In addition, some data suggest the presence of helodermin, galanin, and gastrin releasing peptide (GRP).
(iii). The sensory fibers to the intracranial vasculature have their origin in the trigeminal ganglion and store calcitonin gene-
related peptide (CGRP), amylin, substance P, neurokinin A and B, PACAP, dynophine, and nociception.

The Complexity of the CGRP Family of Peptides
and Their Associated Receptors.Calcitonin (CT)
is a well-known peptide hormone, isolated from
parathyroid glands and shown to be involved in cal-
cium ion homeostasis. Early studies demonstrated a
weak anti-nociceptive effect of salmon CT in pain.
A breakthrough in this field came after cloning of
the CT gene: the gene showed alternative RNA-
processing in neuronal tissues resulting in mRNA
for a related polypeptide named calcitonin gene-
related peptide (CGRP).20 CGRP appears to be
the principle gene product formed in tissues outside
the thyroid21 and it coexists with substance P in
sensory nerves and neurons.18,22 The CGRP family
of peptides consists not only of CGRP but includes
calcitonin (CT), adrenomedullin (AM), and amylin
(AMY),23 and these peptides have been found in
the trigeminal system and to some extent in the
CNS.
The receptors for members of the CGRP pep-
tide family are somewhat unusual in that they con-
sist of the calcitonin receptor-like receptor (CLR),
a G protein-coupled receptor of the B-type that is
linked to one of three receptor activity-modifying
proteins (RAMP). Both components, CLR and
RAMP, are necessary to yield a functional recep-
tor.23 The CGRP receptor consists of CLR and
RAMP1. The adrenomedullin receptors, AM1 and
50
AM2, consist of CLR coupled with either RAMP2
or RAMP3, respectively.23 The calcitonin receptor
(CTR) consists of only CTR. Amylin receptors are
created by linking CTR with a RAMP; amylin
AMY1-3 receptors consist of CTR plus RAMP1, 2,
or 3, respectively. CTR with RAMP1 also responds
to CGRP.
Localization of CGRP and Related Peptides in
the Trigeminal Ganglion.The trigeminovascular
system is involved in the regulation of the cranial
vasculature and is a key element in transmission
of pain. Over the years, the trigeminal system has
become a key focus of efforts to elucidate prima-
ry headache pathophysiology. As pointed out in
Figure 1, there are many potential neuronal mes-
senger molecules in the trigeminal ganglion, and
considerable effort has been made to understand
their relative roles in pain transmission. Initially
the focus was on substance P, driven by the hy-
pothesis that migraine is associated with neuro-
genic inflammation in the dura mater.24 For
decades, substance P was considered to be the
key player in pain responses; however, after a
number of negative clinical trials, this line of
research was abandoned.25
Early work on CGRP demonstrated that this
sensory peptide was present in >50% of the tri-
geminal neurons and in small to medium sized
(C-fibers). In addition, the wide distribution of
CGRP receptors in the trigeminovascular system
is consistent with a role in migraine pathophysiol-
ogy26-28 (Fig. 2). CGRP and CGRP receptor ele-
ments are expressed in trigeminal nerve fibers,
both in central and peripheral branches; however,
the CGRP positive neurons and the CGRP recep-
tor containing neurons are distinct in the trigemi-
nal ganglion as well as in their ramifications, the
C-fibers and A-fibers, respectively. We have dem-
onstrated the presence of mRNA and protein for
two CGRP-responsive receptors, the CGRP and
AMY1 receptors, in neurons of rat and human
trigeminal ganglia.29 In support of this finding,
quantification of agonist and antagonist potencies
reveals a dual population of functional CGRP-
responsive receptors in primary cultures of rat tri-
geminal neurons.
May 2017
Role of CGRP in the Trigeminovascular
Pathway.Cerebrovascular CGRP fibers originate
in the trigeminal ganglion,22 CGRP is a potent vaso-
dilator in different vascular regions, and we showed
that this response occurred in cerebral arteries.
Vasodilation was independent of the endothelium
and was mediated via activation of adenylate
cyclase.30 In vivo CGRP potently dilates cerebral
arterioles, but not cerebral veins, thereby increasing
cerebral blood flow. It is now clear that CGRP is an
essential molecule responsible for maintaining nor-
mal resting tone in the brain circulation.31 Perivascu-
lar CGRP disappears after denervation of the
trigeminal ganglion; but this procedure does not alter
resting cerebral blood flow, flow-metabolism cou-
pling, nor does it modify cerebral autoregulation.31
Instead, the CGRP innervation appears to mediate a
protective vasodilatory reflex triggered in response
to vasoconstriction.32
Our translational work in humans demonstrated
that stimulation of the trigeminal pathway (in neural-
gia patients) caused release of both CGRP and sub-
stance P.33 In a landmark clinical study by Edvinsson
and Goadsby, it was shown that only CGRP is
released in significant amounts during acute migraine
and cluster headache attacks.3,4,34 This study was
possible at the time because we had developed a sen-
sitive radioimmunoassay (RIA) for CGRP and also
realized that the samples must be taken close to the
event (venous outflow from the headthe external
jugular vein) in order to pick up a significant sig-
nal.33,35 It was astonishing that CGRP was the only
peptide/neuronal messenger in the trigeminal system
that significantly correlated with the acute attack.35
Further patient studies supported these findings by
demonstrating increased levels of CGRP in serum,
cerebrospinal fluid, and saliva.34,36 Moreover, the
elevated levels of CGRP normalize after effective
triptan treatment of the migraine attack.4 In chronic
migraine, CGRP seems to be chronically elevated.36
The systemic administration of CGRP to migraine
sufferers triggers a migraine-like attack phenotypi-
cally similar to the subjects spontaneous attack.37
Studies like these paved the way for development of
new migraine drugs aimed at various aspects of the
CGRP transmission.
Headache 51

Fig. 2.Schematic illustration of some of the intracranial sites where the novel CGRP antibodies, the CGRP receptor anti-
body, and gepants putatively have their main site of action: (i). The trigeminal ganglion with neurons and nerve fibers, satellite
glial cells, and blood vessels all have components of the CGRP system. (ii). Dura mater with the meningeal artery and its
branches. (iii). Extracranial structures lack bloodbrain barrier, which allows these agents to interact with the CGRP signaling
at many sites. The central part of the trigeminovascular system, the trigeminal nucleus caudalis, and the spinal cord at C1 and
C2 levels might also be modified by the antibodies and gepants; however, this would more likely be an indirect effect.

CGRP Peptides in Migraine-Associated CNS respectively. To define CGRP receptor binding

Regions.It has been hypothesized that CGRP
acts at second order neurons in the trigeminal
nucleus caudalis (TNC) and at the C1-2 level of the
spinal cord to transmit pain signals to the thalamus
and higher cortical pain regions.38 Also of interest
are certain brainstem areas that are shown with
functional imaging to be activated during migraine
attacks.1,9,10 To study the possible role of CGRP in
the CNS, we used in situ hybridization and immu-
nofluorescence to detect mRNA expression and
cellular localization of CLR and RAMP1,
sites, in vitro autoradiography was performed with
a labelled CGRP receptor antagonist.
CLR and RAMP1 mRNA and protein expres-
sion were detected in a number of relevant regions,
such as periaqueductal gray, area postrema, pontine
raphe nucleus, spinal trigeminal nucleus, and spinal
cord.39 In addition, RAMP1 mRNA expression was
found in the posterior hypothalamus, dorsal raphe
nucleus, pontine nuclei, vagus nerve, inferior olive,
and motor trigeminal nucleus. Protein coexpression
of CLR and RAMP1 was also observed. The
52
findings suggest that several regions in the brain-
stem may be involved in CGRP signaling.39 The
distribution within the CNS of CGRP, CLR, and
RAMP1, however, is not uniform. CGRP appears
most prominently expressed in the soma of neurons
in cortex and cerebellum but there is a scant distri-
bution of CGRP positive fibers in the CNS. CLR
and RAMP1 immunoreactivity appear mostly in
extensive networks of fibers.40 Overall, the analysis
of the distribution of CGRP and its receptor in the
CNS shows a very rich expression; hence numerous
possibilities may exist for involvement of this neu-
ropeptide in brain function in general.39,40
We have recently revealed the complexity in
the CNS of the different elements of the CGRP/CT
system and indeed there is an impressive differen-
tial expression of the receptor components in the
CNS.39,40 The finding of a functional noncanonical
CGRP receptor (AMY1) at neural sites, suggests
this target could be of importance for treating cra-
niofacial pain and also provide another way to tar-
get the CGRP axis in migraine.29 We observed
CTR expression in the human brain stem, specifi-
cally the medulla oblongata. A dense CTR staining
was noted in several discrete nuclei, such as the
nucleus of the solitary tract, hypoglossal nucleus,
cuneate nucleus, spinal trigeminal nucleus, gracile
nucleus, and the inferior olivary nucleus. In addi-
tion, we found CTR staining in the area postrema,
the lateral reticular nucleus, and the pyramidal
tract. Thus, the extensive expression of CTR in the
medulla suggests that CTR may be involved in a
wide range of CNS functions.41 It is likely that all
the members of the CGRP family of peptides will
be found as well as their specific receptor subtypes
in related CNS regions. As yet, however, the
expression pattern is difficult to interpret in terms
of headache and headache treatment.
Where Do the CGRP Blockers Act?.Convincing
evidence for the role of CGRP in migraine pain
came from the development of CGRP receptor
antagonists42 and their subsequent study in clinical
trials.6,7,34 It has been suggested that elevated neu-
ronal RAMP1 could potentially sensitize the tri-
geminal ganglion of individuals to CGRP actions.
However, little is currently known about the
May 2017
regulation of RAMP1 levels in migraine. Published
clinical studies using CGRP receptor antagonists
have all demonstrated clinical efficacy comparable
to that of triptans in the treatment of acute
migraine attacks6,7,34; therefore, it is of great impor-
tance to clarify the sites where drugs blocking
CGRP signaling may have their therapeutic effect.
Because of the BBB and the fact that the size
of the anti-CGRP and anti-CGRP receptor anti-
bodies are very large, the site of their antimigraine
effect is probably outside the BBB.43 We base this
view on several studies: First, autoradiography
showed CGRP binding sites in the trigeminal gan-
glion of rhesus monkey, and this correlated with
localization of CLR/RAMP1.44 Systemic administra-
tion of Evans blue revealed that the trigeminal gan-
glion is not protected by the BBB. This suggests
that molecules do not need to be CNS-penetrant to
block the CGRP receptors.44 Second, a PET study
in monkey and man using a PET tracer (MK-4232),
which displays rapid brain uptake, showed a charac-
teristic regional brain binding at CGRP receptors.45
In a clinically relevant dose of telcagepant (140 mg,
p.o.) there was no displacement seen in the PET
binding of radiolabeled tracer in the CNS. At a
nearly 10 times higher systemic dose of telcagepant,
there was significant displacement of the CGRP
receptor binding in the CNS but at no additional
clinical effect. The main conclusion was that it is
unlikely that antagonism of central CGRP receptors
is required for the efficacy of CGRP blockers in
acute attacks of migraine. Third, direct measure-
ments of the permeability surface area (PS
product 5 lL/min/g tissue) showed >30 times higher
PS product in the TG than in any brain region,
including the trigeminal nucleus caudalis.46
Summarizing the current knowledge, one can
conclude that (i) the trigeminal ganglion and the
dura mater lack BBB, (ii) the trigeminal ganglion
contains receptors for triptans and gepants, (iii) this
ganglion is a key region for transmission of pain
information, eg, to the TNC, and (iv) it innervates
cranial vasculature that responds to various mig-
raine related drugs. Therefore, the trigeminal gan-
glion represents a key structure located strategically
at the base of the brain and central to sensory pain
Headache 53

Fig. 3.Description of the synaptic localization of CGRP receptors and targets for antimigraine effects of triptans, gepants,
and antibodies. Current view suggests that (i) the triptan receptors (5-HT1B/1D) are presynaptic and inhibit the release of
CGRP. (ii) The gepants are competitive receptor antagonists at the postsynaptic CGRP receptor and thereby limit is effects.
(iii) The CGRP receptor antibody binds to the two extracellular domains of the CGRP receptor, CLR and RAMP1, irrevers-
ibly, and thereby reduces synaptic transmission signaling. (iv) The CGRP antibodies act like as sink in the signaling and bind
CGRP molecules wherever they find these molecules; they do not discriminate between a- or b-CGRP.

neurotransmission. It consists of neurons of various
sizes (10%) and a large population of satellite glial
cells (90%). In addition, there are CGRP contain-
ing nerve fibers within the trigeminal ganglion, pro-
viding a morphological basis for interaction
between the different cells in the ganglion (Fig. 3).
Considering all of the above, CGRP is established
to be the key player in understanding migraine
pathophysiology. Furthermore, it appears evident
that the targets of CGRP reside outside the BBB.
With this current knowledge, the drive to fully
understand the development of migraine should
focus on these structures, with particular focus on
the common denominator: the trigeminal ganglion.
STATEMENT OF AUTHORSHIP
The author conceived and wrote the manuscript
in all aspects.
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