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Calcitonin gene-related peptide: relevance for migraine 

Calcitonin gene-related peptide: relevance for migraine
Calcitonin gene-related peptide: relevance for migraine

Jes Olesen

and Inger Jansen-Olesen

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date: 19 November 2018

Migraine is a disorder without any patho-anatomical correlate. This has made the scientific study of migraine difficult but, on the other hand, holds the promise that the condition may be fully reversible by adequate pharmacological intervention. The origin of nociceptive activity in migraine is in all likelihood the sensory nerve terminals around blood vessels in the brain and/or in the extracranial tissues of the head. Considerable interest has therefore been directed towards identifying signalling molecules in the perivascular nerves and in the blood vessels of the head as well as identifying their receptors and related mechanisms such as ion channels and second messengers. For this purpose animal models are important but, because of species differences, human studies are indispensable. It is from a combination of animal experimental studies and human studies that evidence has been accumulating to suggest that calcitonin gene-related peptide (CGRP) may be crucial in migraine. The following chapter will give an outline of the different studies that have led to the current high level of interest in CGRP antagonism as a possible new treatment principle in migraine.

From a historical point of view, Lars Edvinsson was the driving force behind the elucidation of CGRP's distribution in the cranial circulation (Figure 13.1) and in the evaluation of its basic effects and receptor mechanisms1–6 (Figure 13.2). His basic studies led him to suggest that CGRP may play a part in migraine pathophysiology. This was later confirmed in human studies.7–9

Fig. 13.1 Whole-mount preparation from rat cerebral arteries showing a moderately dense network of nerve fibres containing calcitonin gene-related peptide. Reproduced with courtesy of Helle Wulf.

Fig. 13.1
Whole-mount preparation from rat cerebral arteries showing a moderately dense network of nerve fibres containing calcitonin gene-related peptide. Reproduced with courtesy of Helle Wulf.

Fig. 13.2 Relaxant responses in human cerebral and middle meningeal arteries pre-contracted by 3 × 10–6 M prostaglandin F2a to the cumulative application of human α‎-CGRP with and without the antagonist human α‎-CGRP8–37 (10–6 M – 3 × 10–6 M). Values given represent mean ±SEM, n = 4–11. CGRP, calcitonin gene-related peptide. Reproduced from the European Journal of Pharmacology, 481(2–3), Jansen-Olesen, et al. In-depth characterization of CGRP receptors in human intracranial arteries (2003), pp. 207–216 with permission from Elsevier.

Fig. 13.2
Relaxant responses in human cerebral and middle meningeal arteries pre-contracted by 3 × 10–6 M prostaglandin F2a to the cumulative application of human α‎-CGRP with and without the antagonist human α‎-CGRP8–37 (10–6 M – 3 × 10–6 M). Values given represent mean ±SEM, n = 4–11. CGRP, calcitonin gene-related peptide. Reproduced from the European Journal of Pharmacology, 481(2–3), Jansen-Olesen, et al. In-depth characterization of CGRP receptors in human intracranial arteries (2003), pp. 207–216 with permission from Elsevier.

Calcitonin gene-related peptide and its receptors

CGRP was cloned by Amara and co-workers in 1982 and is a 37 amino acid peptide with amino and carboxyl terminals.10 Based on rat CGRP, the human homologue was isolated in 1984.11 It is present in an α‎ and a β‎ form that derive from separate genes.12 The two CGRP subtypes are in general equally distributed within the central and peripheral nervous system.12,13 However, the amount of mRNA for α‎-CGRP is ten times higher and the actual concentration of α‎-CGRP is three to six times higher in the trigeminal ganglion and the primary sensory neurons and nerve terminals.12,14 CGRP is most abundant in the posterior horn and in primary sensory neurons of the spinal cord and in the trigeminal system where it is co-localized with substance P.15 CGRP-containing nerve fibres have been identified throughout the cardiovascular system16,17 but they are primarily located in sensory nerve terminals around blood vessels and more so in the cranial circulation.6 Circulating CGRP is found in human plasma.18–20 It can be released by electrical stimulation of sensory nerves.19 Bradykinins have been shown to increase CGRP release21–23 and so may prostaglandins.24

CGRP receptors that are blocked by CGRP8–37 were previously called CGRP1 receptors and those not blocked were called CGRP2 receptors.25,26 The molecular biology of the CGRP2 receptors has not been worked out; thus there is still an uncertain nature of this receptor. Furthermore, the use of peptide antagonists to classify CGRP receptors has subsequently been criticized and as experimental conditions may change the actions of these peptides their ability to reliably discriminate between CGRP receptor subtypes will be limited.27 CGRP receptors comprise the calcitonin-receptor-like receptor (CALCRL) co-expressed with a receptor activity-modifying protein (RAMP).28 The latter are small proteins containing a single membrane spanning domain, a large extracellular domain, and a short cytoplasm domain. Co-expression of CALCRL with RAMP1 forms CGRP receptors, whereas co-expression with RAMP2 or RAMP3 forms receptors for adrenomedullin.29,30 It has been suggested that functional CGRP receptors may require another protein called receptor component protein (RCP).31

Function of calcitonin gene-related peptide

Infused intravenously, CGRP causes marked increase in heart rate, a decrease in blood pressure, and flushing of the face as well as headache.32–34 These responses are dose-dependent and limited by the systemic vascular effects. Infusion of CGRP also causes a slight increase in cerebral blood flow and slight dilatation of the middle cerebral artery in humans while the superficial temporal artery is markedly dilated.34 Infusion of the CGRP antagonist olcegepant has no effect on systemic haemodynamic parameters in humans,35 illustrating that CGRP is not normally leaking out of perivascular nerve terminals and that CGRP does not participate in the multiple dilator and constrictor actions that tightly control normal vascular diameter. Pretreatment with olcegepant totally and completely abolished all effects of infused CGRP in humans.34 Animal experimental studies have demonstrated strong vasodilator action of CGRP on isolated blood vessels and in a close cranial window model in the rat. In the latter model, CGRP dilated the middle meningeal artery while an effect on brain arteries was probably secondary to systemic blood pressure decrease.36 In studies with perfused cerebral arteries, CGRP was only active from the adventitial side and not when given intraluminally.37,38 Like in humans the blocker olcegepant completely blocked any effect of CGRP infusion in rats.36

Calcitonin gene-related peptide in blood

CGRP levels in blood have generally been very stable and only a few diseases are known to alter circulating CGRP levels. It therefore created enormous interest, when it was first published that CGRP was increased in the external jugular venous blood but not in cubital fossa blood during a migraine attack.8 When measured in another group of patients after sumatriptan treatment, CGRP was normal in both studies. Values in patients were compared with values in a control group and no intrapatient comparison was made.8,39 Subsequently, an Italian study also found increased CGRP in external jugular blood but, in contrast to the study of Goadsby et al., also in blood from the cubital fossa.40 Based on animal studies plus the presumed increase of CGRP during migraine, Boehringer Ingelheim developed the first selective non-peptide CGRP antagonist, olcegepant, also known as BIBN4096BS.

Glyceryl trinitrate induces attacks in migraine sufferers.41 We therefore measured CGRP in the jugular venous blood before and after glyceryl trinitrate in rat but found no difference.42 These studies led us to consider that the published literature on CGRP release needed to be further studied. While the initial studies were all comparing patient data with historic controls, we used patients as their own controls by studying CGRP in the external jugular and cubital fossa blood during attack as well as outside of attack. In this study we found no indication of increased CGRP during attack. To guard against any difference in assay, we used the exact same assay as in the previous studies plus another better validated assay. We did extensive analyses of these materials showing that duration of attack, age or sex of patients, severity of pain, and other factors were not associated with increased CGRP. It therefore remains an open question whether CGRP is ever increased during migraine attack and, if so, under which circumstances and in which patients it may be increased.20 One major difference between our study and the previous studies was that we took blood in the patient's own home under considerably more comfortable conditions than in the previous study where patients had been desperate enough to go to an emergency room with their migraine attack.8 The latter situation could be considerably more stressful and stress is known to increase CGRP.43 If that was the explanation one would, however, expect CGRP to increase both in external jugular venous blood and in cubital fossa blood.

Is calcitonin gene-related peptide able to activate nociceptors?

CGRP is present within nociceptive pathways both peripherally and in the central nervous system. However, the role of CGRP in nociception is not fully understood. We were unable to show any nociceptive effect of CGRP when injected intradermally in human subjects, and CGRP did not even have an additive effect when combined with nociceptive substances.44 Similarly, CGRP applied to dura mater was unable to sensitize peripheral sensory nerve endings and also unable to sensitize nociceptive neurons in the brain.45 It remains unclear, therefore, how CGRP could be involved in the nociceptive mechanisms of migraine. One possible mechanism that does not seem to be involved is neurogenic inflammation. Although stimulation of the trigeminal ganglion results in leaking of plasma proteins from the vascular space into the dura mater (neurogenic inflammation) this is not caused by CGRP but by liberation of substance P. Consistent with this, the plasma extravasation was abolished in tachykinin neurokinin 1 receptor knockout mice after mustard oil application while vasodilatation was enhanced. In α‎-CGRP knockout mice, mustard oil caused plasma extravasation and vasodilatation that was inhibited by treatment with a neurokinin 1 receptor.46

Calcitonin gene-related peptide can induce migraine headache

CGRP infusion into normal experimental subjects reliably causes mild headache concomitant with vascular responses as described above.34 When CGRP was infused into subjects with migraine without aura, it induced a more pronounced headache followed by a delayed increase in headache. Three of ten subjects fulfilled all the criteria for migraine without aura attack according to the International Headache Society. In patients where the headache did not quite fulfil criteria for migraine, it was still migraine-like.47 The study demonstrated beyond doubt that, with regard to headache and migraine, CGRP is a nociceptive molecule. However, the site of this action remains uncertain. There were slight but significant changes in cerebral blood flow and in the diameter of the middle cerebral artery. In addition another study showed that the superficial temporal artery dilated markedly after CGRP infusion.34 Unfortunately the middle meningeal artery could not be measured in these human studies, but it is likely that it was markedly dilated because it bears more resemblance to the superficial temporal artery than to the cerebral arteries. Another important fact is that the non-peptide CGRP receptor antagonist olcegepant completely prevented CGRP induced headache.34 Olcegepant is a large water-soluble molecule that does not readily pass the blood–brain barrier. However, it is an extremely potent molecule and the dose used clinically is high compared with doses used to block arterial dilatation in experimental studies.9,34–36 Therefore, an intracerebral site of action of olcegepant cannot be ruled out. However, if this is true a lower dose of olcegepant should be sufficient to block peripheral CGRP effects. In a recent study, the effect of compound 3, an equipotent analogue of olcegepant, blocked the increase in dermal blood flow after topical application of capsaicin. In rhesus monkey a maximum inhibition was observed at 30 µg/kg or 2.1 mg/70 kg, which corresponds well to the dose (2.5 mg) used in humans.48

Calcitonin gene-related peptide receptor blocking is effective in acute migraine attacks

The final proof of the importance of CGRP in migraine came from a therapeutic study.9 Olcegepant as mentioned before is a highly selective and highly potent CGRP receptor antagonist. In a phase 2 study olcegepant dose-dependently alleviated symptoms of a migraine attack. An adaptive design was used whereby the dose was increased or decreased in each block of patients depending on the response in the previous block. The study identified doses of 2.5, 5, and 10 mg as highly effective and 2.5 mg was chosen as the preferred dose for future studies9 (Figure 13.3). However, the development of the compound was stopped because of difficulties of absorption and no further treatment data are available. This remarkable proof of concept study has, however, stirred even more interest in CGRP and migraine than before. CGRP antagonists that are orally available are therefore awaited with great excitement and hopefully will turn out to become an important class of new migraine drugs.

Fig. 13.3 Headache response (moderate or severe headache at baseline becoming nil or mild at 2 hours post-dose) rates for each dose of BIBN4096 tested, the placebo response rate, and the pooled active drug rate.

Fig. 13.3
Headache response (moderate or severe headache at baseline becoming nil or mild at 2 hours post-dose) rates for each dose of BIBN4096 tested, the placebo response rate, and the pooled active drug rate.


The development of a non-peptide CGRP antagonist represents the first truly mechanism- based drug development for migraine. This development was based on almost two decades of basic and clinical research. Animal experiments and studies of human arteries demonstrated the location and effects of CGRP and its receptors as well as the effect of CGRP receptor blockade. The result suggested that CGRP is present in the sensory nervous system that is an area related to migraine and that it is a strong vasodilator. Crucial studies were then done in humans. First, increased release of CGRP during the migraine attack was suggested, although later studies found no such increase. Secondly, it was shown that CGRP infusion can induce vascular type headache in normal volunteers and in migraine subjects. Furthermore, in migraine subjects CGRP induced migraine attacks without aura. The final proof of the importance of CGRP in migraine came from a phase 2 study demonstrating that olcegepant, a non-peptide CGRP antagonist, had a highly significant effect in acute migraine attacks. It is extremely promising that mechanism-based drug development for migraine is now possible and more examples may soon follow the pioneering work on CGRP.


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