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CGRP Receptor Antagonists in the Treatment of Migraine
Paul L. Durham and Carrie V. Vause
Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO
Abstract
Based on preclinical and clinical studies, the neuropeptide calcitonin gene-related peptide (CGRP)
is proposed to play a central role in the underlying pathology of migraine. CGRP and its receptor
are widely expressed in both the peripheral and central nervous system by multiple cell types
involved in the regulation of inflammatory and nociceptive responses. Peripheral release of CGRP
from trigeminal nerve fibers within the dura and from the cell body of trigeminal ganglion neurons
is likely to contribute to peripheral sensitization of trigeminal nociceptors. Similarly, the release of
CGRP within the trigeminal nucleus caudalis can facilitate activation of nociceptive second order
neurons and glial cells. Thus, CGRP is involved in the development and maintenance of persistent
pain, central sensitization, and allodynia, events characteristic of migraine pathology. In contrast,
CGRP release within the brain is likely to function in an anti-nociceptive capacity. This review
will focus on the development and clinical data on CGRP receptor antagonists as well as
discussing their potential roles in migraine therapy via modulation of multiple cell types within the
peripheral and central nervous systems.
Keywords
migraine; trigeminal ganglion; RAMP1; sensitization
Migraine is a complex neurovascular disorder that affects 12% of the general
population [1–3] and is characterized by intense head pain that can be accompanied with
sensitivity to light (photophobia), sound (phonophobia), and nausea. Activation of the
trigeminovascular system is believed to be a primary pathway leading to the pain associated
with migraine. The trigeminovascular system is comprised of nociceptive nerves from the
first or ophthalmic region of trigeminal ganglia, the major vessels responsible for regulating
cerebral blood flow, and the smaller vessels in the pain-sensitive covering of the brain,
known as the meninges [4]. The trigeminal ganglion consists of psuedounipolar nerve cells,
primarily Aδ and C-fibers, that are responsible for transmission of nociceptive information
originating from meningeal blood vessels to the caudal brain stem or high cervical cord that
leads to headache pain [5–9]. While the mechanism by which a migraine attack is initiated is
not well understood, dysfunction in the central nervous system (CNS) leading to release of
inflammatory mediators is proposed to cause sensitization and excitation of trigeminal
nerves that promote neurogenic inflammation and generation of painful stimuli [10–13].
Activation of trigeminal nociceptors mediates the release of neuropeptides, such as
calcitonin gene-related peptide (CGRP), substance P, and neurokinin A, from primary
sensory nerve fibers that are involved in pain transmission [14–16].
Correspondence should be addressed to Paul L. Durham, Center for Biomedical & Life Sciences, Missouri State University,
Springfield, MO 65806. Phone: (417) 836-4869 Fax: (417) 836-7602 pauldurham@missouristate.edu.
NIH Public Access
Author Manuscript
CNS Drugs. Author manuscript; available in PMC 2011 July 18.
Published in final edited form as:
CNS Drugs
. 2010 July 1; 24(7): 539–548. doi:10.2165/11534920-000000000-00000.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
1. CGRP and Migraine
Based on theories on migraine pathology, activation of trigeminal ganglion nociceptive
neurons and the subsequent release of CGRP, but not substance P or neurokinin A, are
implicated in migraine pathology [17, 18]. In humans, CGRP exists in two forms that are
termed α-CGRP and β-CGRP, which are derived from separate genes and differ by three
amino acids yet exhibit similar biological functions [19–22]. The 37-amino acid neuropeptide
α-CGRP, which arises from alternative splicing of the calcitonin-CGRP gene [23], is the
main form expressed in trigeminal ganglia neurons [19] and the form most essential to
migraine pathology. In contrast, β-CGRP, which is encoded by a different gene that is highly
homologous to the calcitonin-CGRP gene, is primarily expressed in enteric nerves and in the
pituitary gland [24] and its role, if any, in migraine is not known. Thus, the focus of this
review will be on understanding the role of α-CGRP, which will be referred to simply as
CGRP, and activation of the CGRP receptor in migraine pathology.
CGRP is widely distributed in the central and peripheral nervous system [22] where it is
predominantly expressed in C and Aδ nerve fibers that transmit nociceptive signals to the
central nervous system (CNS) [12]. Although a complete understanding of the pathogenesis
of migraine is not clear, several lines of evidence in migraineurs support a role of CGRP as a
key mediator of migraine pathology. For example, CGRP levels in the cranial circulation as
well as in saliva are increased during a migraine attack [25–27]. Further evidence for CGRP
having a central role in migraine has been demonstrated by data from studies showing that
successful treatment of migraine headache pain with the 5-hydroxytryptamine1B/1D agonist
sumatriptan, as well as other triptan drugs, resulted in the normalization of CGRP
levels [27, 28]. Finally, compelling proof for a central role of CGRP in migraine was obtained
with the demonstration that infusion of human CGRP could provoke a migraine attack in
susceptible individuals [29] and intravenous administration of the potent CGRP receptor
antagonist olcegepant (BIBN4096BS) could abort acute migraine attacks to a comparable
degree as reported for sumatriptan [30].
Based on the cellular expression of CGRP and its receptor, CGRP is thought to contribute to
the underlying pathology of migraine at multiple sites within the trigeminovascular
system [12, 13]. For example, CGRP released from fibers that are associated with meningeal
vessels is thought to mediate vasodilation and mast cell degranulation. Activation of the
platelets and mast cell degranulation would lead to the release of pro-inflammatory agents
that mediate sensitization of trigeminal nociceptors and may be involved in sustaining the
painful phase of migraine [31]. The sterile inflammatory process is thought to cause
sensitization of the nerve fibers, thus lowering the pain response threshold to previously
innocuous stimuli, such as blood vessel pulsations and head movements [32, 33]. Following
trigeminal nerve activation, CGRP would be released from fibers projecting to the
trigeminal nucleus caudalis that facilitate excitation of second order neurons and glial cells
involved in the initiation and maintenance of persistent pain. In addition, CGRP released
from the cell body (soma) of trigeminal neurons is thought to act in an autocrine manner to
stimulate its own synthesis as well as function in a paracrine manner to stimulate cytokine
production in satellite glial cells [34, 35]. CGRP release from trigeminal ganglion nerve cell
bodies would induce further CGRP synthesis as well as stimulate satellite glial cells to
release inflammatory cytokines and nitric oxide that would promote peripheral sensitization
of trigeminal nociceptors. The involvement of CGRP in peripheral and spinal nociceptive
mechanisms is well established [36–42]. Spinal application of CGRP facilitates nociceptive
behavior [39, 41, 43] and sensitizes the responses of dorsal horn neurons to innocuous and
noxious peripheral stimulation [38, 41, 44]. In addition, blockage of CGRP receptors with the
peptide antagonist (CGRP8–37) or antiserum resulted in anti-nociception in animal models of
inflammatory [40] or central neuropathic pain [45]. Taken together, results from these studies
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support an important role of CGRP in the development and maintenance of peripheral
sensitization of trigeminal ganglion neurons and central sensitization of second order
neurons, which are key pathophysiological events associated with migraine. Given the
central role of CGRP in migraine, blocking the physiological effects of CGRP would be a
logical therapeutic target.
2. CGRP Receptor
Although historically CGRP receptors have been divided into two classes referred to as
CGRP1 and CGRP2, recent data have clarified that the CGRP1 receptor is the only CGRP
receptor [46]. Functional CGRP receptors are composed of a G protein-coupled receptor
known as the calcitonin-like receptor (CLR), a single transmembrane domain protein called
receptor activity modifying protein type 1 (RAMP1), and a receptor component protein
(RCP) that defines the G-protein to which the receptor couples [47]. RAMP1 is essential for
the formation of functional CGRP receptors since it is responsible for trafficking mature
CLR proteins to the surface of the cell membrane as well as defining the relative potency of
ligands for the receptor [48]. While structure-function investigations have demonstrated that
an 18 amino acid sequence located at the N-terminus of the CLR is important for CGRP
docking, it does not appear to be involved in the activation of the mature CGRP
receptor [49]. In contrast, binding studies have demonstrated that the first seven N-terminal
amino acids are essential for receptor activation [50]. Importantly, while deletion of amino
acids 2 and 7 that are involved in the formation of a disulfide bridge does not affect receptor
affinity, deletion of these amino acids resulted in a total loss of biological activity of the
CGRP receptor [51]. Given these findings, it is not too surprising that the first CGRP
receptor antagonists were N-terminal truncated fragments of the CGRP peptide [52].
CGRP8–37, which includes all but the first seven amino acids of the normal peptide,
functions as an antagonist of CGRP receptors by blocking binding of endogenous full-length
CGRP. Although CGRP8–37 has been demonstrated to inhibit vasodilation and neurogenic
inflammation in animal models, its clinical effectiveness is severely limited due to its short
half-life [53] that contributes to its lack of potency in vivo. While other truncated CGRP
analogs with higher affinities for CGRP receptors have been developed, they have also not
proven useful in clinical studies because of similar limitations [54]. Although these results
clearly demonstrated that truncated forms of CGRP might not be clinically useful,
information gained from these studies provided convincing evidence to support the
development of non-peptide molecules to inhibit CGRP receptor function for the treatment
of migraine.
CGRP receptors are expressed by multiple different cell types within the nervous,
cardiovascular, and immune systems that are thought to play important roles in migraine
pathology. For example, CGRP receptors have been reported on neurons and glia in the
peripheral and central nervous systems, including second order neurons and
astrocytes [55, 56] as well as trigeminal ganglion neurons [35, 57] and satellite glial cells [34].
In addition, CGRP receptors are present on meningeal smooth muscle cells [58, 59] and the
larger cerebral blood vessels [60, 61]. Another site of CGRP receptors is mast cells found
within the dura mater [31, 62].
3. CGRP Receptor Antagonists
3.1 Olcegepant (BIBN4096BS)
The first potent and selective non-peptide antagonist of the human CGRP receptor was
originally referred to as BIBN4096BS, but has been renamed olcegepant [63, 64]. The
particular affinity of olcegepant for the CGRP receptor has been shown to dependent on
residues within the extracellular region of RAMP1 rather than the CLR or RCP subunits [48].
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Since this site is required for selective binding of CGRP, olcegepant functions as a CGRP
receptor antagonist by directly competing for the binding site of the endogenous ligand
CGRP and therefore, inhibits the physiological and cellular effects of CGRP. Information
obtained from in vitro and animal studies, which have recently been summarized in several
comprehensive review articles [65, 66], demonstrated that olcegepant could repress the
stimulatory effects of CGRP on isolated and intact blood vessels [67–69]. However,
olcegepant was shown to lack vasoconstrictive effects based on a study in which infusion of
olcegepant to healthy volunteers caused no significant systemic or cerebral blood flow
changes [70]. More recently, olcegepant was shown to suppress the stimulatory effect of
CGRP on its own synthesis in trigeminal ganglion neurons, an event thought to function in
an autocrine manner such that CGRP release from neuronal cell bodies stimulates its own
further synthesis [71].
Importantly, results from a phase IIa clinical trial on olcegepant provided the first direct
evidence to support the use of a non-peptide CGRP receptor antagonist as an abortive
therapy of migraine [30]. Findings from that clinical proof-of-concept study not only
demonstrated that olcegepant was as effective as oral triptans, which are regarded as the
most effective class of abortive anti-migraine drugs, but also demonstrated its safety and
minimal adverse event profile [72]. In particular, the finding that olcegepant appeared to lack
cardiovascular side effects such as changes in basal blood pressure or heart rate [30, 67] may
prove to be advantageous for this new class of compounds. While results from clinical
studies demonstrated that olcegepant was effective in treating spontaneous migraine
attacks [30] and CGRP-induced headache [73], a major limitation for the usefulness of this
hydrophilic compound was that fact that it had to be administered by intravenous injection.
4.2 Telcegepant (MK-0974)
To facilitate a more useful delivery method, Merck Research Laboratories undertook a
research program to discover compounds that were potent oral CGRP receptor
antagonists [74]. One compound that was identified using this approach was the selective
CGRP receptor antagonist, MK-0974, which has now been renamed telcagepant [75].
Findings from pharmacological studies have shown that telcagepant is a highly selective,
potent oral antagonist of the human CGRP receptor [76, 77]. Telcagepant, at nM
concentrations, has been reported to repress CGRP stimulated cAMP responses in HEK293
cells that express the human CGRP receptor [78]. The efficacy and safety profile of
telcagepant in the acute treatment of migraine was initially demonstrated in a phase II
clinical [79]. In that study, telcagepant (MK-0974) was shown to be effective and generally
well-tolerated for treating moderate to severe migraine attacks with a primary endpoint of
pain relief at 2 hours [79, 80]. The reported outcomes for telcagepant were comparable to
those of rizatriptan and were significantly superior to placebo. Telcagepant also displayed
superior efficacy vs. placebo for secondary endpoints such as sustained pain relief at 24
hours and sustained pain freedom at 24 hours as well as providing relief of migraine-
associated symptoms such as photophobia, phonophobia and nausea. Furthermore, the
incidence of the most often reported adverse events for telcagepant, which included nausea,
dizziness, and somnolence, were similar to the placebo group. Similar results, such as
efficacy similar to triptans and few associated adverse events, were obtained from a larger
randomized, parallel-treatment, placebo-controlled, double-blind, trial conducted at sites in
both Europe and the United States of America [79]. More definitive proof for the efficacy of
telcagepant was recently provided by data from a large phase III clinical trial [81]. Results
from this study clearly demonstrate the effectiveness of telcagepant to relieve the pain and
other migraine symptoms at 2 hours as well as providing sustained pain relief for up to 24
hours. In addition, telcagepant was found to be generally well tolerated.
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Despite the positive clinical data supporting the use of telcagepant in the acute treatment of
migraine, Merck Research Laboratories recently issued a press release stating that the
company will not file an application to the FDA for telcagepant in 2009. The decision to
suspend further development and testing of this compound was based on findings from a
phase IIA exploratory study in which a small number of patients taking telcagepant twice
daily for three months for the prevention of migraine had marked elevations in liver
transaminases [82]. Thus, it will be important to determine whether the liver toxicity is
related to the particular compound, which is a member of the azepanone-based family of
CGRP receptor antagonists, or whether it is a class effect. Encouragingly, other members of
this family have recently been modified to retain the potency of telcagepant and yet
minimize the susceptibility to oxidative metabolism believed to be involved in hepatic
toxicity [83].
4. CGRP receptor antagonists: numerous cellular targets for migraine
therapy
Given the localization of functional CGRP receptors on multiple diverse cell types
implicated in the underlying pathology of migraine, the beneficial effects of CGRP receptor
antagonists in the acute treatment of migraine likely involves repressing the function of cells
located in peripheral tissues as well as in the CNS (Table 1). Based on preclinical data,
blocking CGRP receptor activation would be expected to affect the function of vascular
smooth muscle cells, mast cells, trigeminal ganglion neurons, glial cells, and second-order
neurons within the CNS. If the headache phase of migraine is dependent on nociceptive
input from perivascular sensory nerve fibers as recently proposed [84], then inhibiting
dilation of human cerebral and meningeal vessels, which express functional CLR and
RAMP1 proteins [58, 59], by blocking CGRP receptor function would be beneficial.
Similarly, inhibiting activity of CGRP receptors that are expressed by dural mast cells [31]
would prevent mast cell degranulation and the subsequent release of histamine and other
pro-inflammatory agents known to cause peripheral sensitization of trigeminal
nociceptors [85]. Other likely peripheral targets of CGRP antagonists would be the neuronal
cell body and associated satellite glial cells located within the trigeminal ganglion since both
of these cells express functional CGRP receptors [71, 86, 87]. While blocking the CGRP
receptors on trigeminal neuron cell bodies would prevent further synthesis of CGRP,
inhibition of CGRP receptors on satellite glial cells would repress the stimulated release of
cytokines as well as nitric oxide [34, 86, 87], which can cause sensitization and activation of
trigeminal neurons [58, 59, 88, 89]. Thus, CGRP antagonists would function to block further
production and release of CGRP from trigeminal neurons by both direct as well as well
indirect mechanisms. Inhibition of CGRP receptors on second order sensory neurons within
trigeminal nuclei in the caudal brain stem and upper cervical spinal cord [56] would directly
block further nociceptive signaling in the CNS and, thus, prevent the development of central
sensitization and hyperalgesia. Furthermore, CGRP antagonists might also function to
directly inhibit NMDA-evoked membrane currents and even reverse sensitization of
nociceptive neurons located in the laterocapsular part of the central nucleus (CeLC) [90, 91],
which is the target of the spino-parabrachio-amygdaloid pain pathway [92]. In addition,
CGRP antagonists would be expected to block stimulation of astrocytes and microglia,
which play prominent roles in central sensitization and persistent pain at the level of the
TNC [93–98]. Taken together, CGRP receptor antagonists would be predicted to inhibit
cellular events that lead to peripheral sensitization and activation of trigeminal ganglion
neurons as well as central sensitization of nociceptive neurons in the TNC and amygdala.
Thus, blockage of CGRP receptors would be expected to inhibit the inflammatory and
nociceptive effects of CGRP at multiple sites within the peripheral and central nervous
systems that are implicated in the underlying pathology of migraine.
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Based on the localization of CGRP receptors in different regions of the brain thought to
inhibit nociception, not all the actions of a CGRP receptor antagonist would be expected to
exert an anti-inflammatory or anti-nociceptive effect (Table 1). This might be especially true
for antagonists that can readily cross the blood brain barrier and thus, directly affect neurons
in regions within the brain. Interestingly, CGRP receptors are present on neurons located in
the nucleus raphe magnus, periaqueductual grey, nucleus accumbens, and central nucleus of
amygadala, which are all thought to inhibit nociception in response to noxious stimuli [99].
Thus, it might be proposed that CGRP receptor antagonist might actually worsen a migraine
attack by blocking the anti-nociceptive actions of these neurons. However, data from clinical
studies on olcegepant and telcagepant do not support such a direct role. Indeed, additional
studies are required to more clearly delineate the physiological effects of blocking CGRP
receptors within the brain.
5. Conclusions
Based on experimental and clinical studies, CGRP is believed to play an important role in
the generation of pain during migraine attacks by facilitating cellular events that contribute
to sensitization of peripheral and central neurons involved in nociceptive transmission. In
support of a central role of CGRP and activation of its receptor in migraine pathology, the
non-peptide CGRP receptor antagonists olcegepant and telcagepant have been shown to be
effective in the acute treatment of migraine. Unfortunately, both compounds are no longer
being pursued as frontline abortive migraine drugs. However, data from the clinical studies
on these compounds has clearly demonstrated the potential therapeutic benefit of this class
of drugs and supports the future development of CGRP antagonists to treat migraine and
possibly other types of chronic pain.
Acknowledgments
Dr. Durham serves on a scientific advisory board, has received grant support, and has served as a consultant for
Merck & Co., Inc.
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Table 1
Proposed function of CGRP antagonists based on localization of RAMP1 location and/or functional CGRP receptors.
Location Cell Type Proposed Function of CGRP Antagonist Binding
Dura Smooth muscle cells Block vasodilation of meningeal vessels, decrease inflammatory response
Dura Mast cells Prevent mast cell activation and secretion of vasoactive, inflammatory, and sensitizing molecules (Lennerz et al., 2008)
Trigeminal ganglion (TG) Neurons Suppress sensitization of primary afferents
TG Satellite glia Repress sensitization and activation of primary nociceptive neurons
Trigeminal nucleus caudalis(TNC) Neurons Inhibit sensitization of second order neurons (Williamson et al., 2001)
TNC Astrocytes Repress astrocyte activation and stimulation of c-fos and cAMP (Reddington et al., 1995)
TNC Microglia Suppress microglial activation and stimulation of c-fos and cAMP (Reddington et al., 1995)
Laterocapsular part of central nucleus (CeLC) Neurons Inhibit NMDA-evoked membrane currents, reverse sensitization of nociceptive CeCL neurons (Han et al., 2005)
Nucleus raphe magnus(NRM) Neurons Post-synaptic inhibition of nociception in the dorsal longitudinal tract (Yu et al., 2009)
Periaqueductal grey (PAG) Neurons Block descending analgesic pathway to the dorsal horn of the spinal cord (Yu et al., 2009)
Nucleus accumbens (NaC) Neurons Binds endogenous CGRP to induce antinociception during noxious stimulation (Yu et al., 2009)
Central nucleus of amygdala (CeA) Neurons CGRP innervation of met-enkephalin-ergic neurons projecting from CeA to PAG (Yu et al., 2009)
CNS Drugs. Author manuscript; available in PMC 2011 July 18.
