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Pathophysiology of migraine: A role for neuropeptides
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 3, No. 3 2006
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Pain MECHANISMS
Pathophysiology of migraine: A role for neuropeptides Stefan Just*, Kirsten Arndt, Thomas Weiser, Henri Doods CNS Research, Boehringer Ingelheim Pharma KG, 88397 Biberach an der Riss, Germany
Migraine is a common debilitating neurovascular disorder. Because of their dual role in modulating neuronal and vascular events, neuropeptides have been
Section Editors: Frank Porreca – University of Arizona, Tucson, USA Michael Ossipov – University of Arizona, Tucson, USA
implied to be of importance in migraine pathophysiology. Most clinical trials investigating neuropeptide receptor ligands for the treatment of migraine, however, did not show the desired results. The only exception so far is Olcegepant (BIBN4096BS), a potent and selective antagonist of the calcitonin gene related peptide (CGRP) receptor. In a clinical study, this compound proved to be effective in treating migraine headache, highlighting the essential role of CGRP for pathophysiology of migraine.
Introduction Migraine is a common episodic headache disorder. The disease can be divided into two major sub-types, namely common migraine and migraine with aura. The common migraine is defined as a recurrent, unilateral headache disorder manifesting in attacks lasting 4–72 h. The pain is of pulsating quality, moderate to severe intensity and associated with nausea and/or PHOTOPHOBIA and PHONOPHOBIA (see glossary) [1]. Migraine with aura is characterized by a headache with features of the common migraine with reversible focal neurological symptoms (like scintillation scotoma; see glossary) that develop before the headache and last up to 60 min [1]. Within Europe and the Americas approximately 6–8% of men and 15–22% of women suffer from migraine, with *Corresponding author: S. Just ([email protected]) 1740-6765/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2006.07.002
women being three times more frequently affected than men. In both sexes, the prevalence peaks at about 40 years of age. Migraine headache leads to high indirect costs because of reduced productivity and due to absenteeism. In addition, annual direct medical costs for migraine care are about $ 1 billion in the USA. Therefore, the impact of migraine on healthcare resource utilization and work loss is very high [2,3]. Currently, mild migraine attacks are most frequently treated with analgesics like nonsteroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are treated with ergots or specific 5HT1B/D agonists, the so-called triptans (named after the first compound with this mechanism of action, sumatriptan (Glaxo Smith Kline); see Table 1) [4]. An important recent clinical trial has shown that sumatriptan was only slightly more effective than an NSAIDs in reducing migraine pain [5]. The main drawbacks of all current treatment options are latency until improvement of headache, incomplete and inconsistent pain relief, as well as recurrence of headache. Furthermore, the medications exhibit the risk of cardiovascular or intestinal side effects [6]. Therefore, there is still much room for improvement of abortive migraine treatment. Medications for the prophylaxis of migraine are available, but such drugs (e.g. topiramate) cause unwanted effects and only reduce the number of migraine attacks without suppressing migraine completely [7]. To overcome these drawbacks, novel treatment options would be desirable. 327
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Glossary Allodynia: exaggerated response to otherwise non-noxious stimuli. Migraine is often associated with thermal and mechanical hyperresponsiveness within the periorbital region. Antidromic stimulation: stimulation of a nerve fibre which induces action potential propagation opposite to the normal direction (e. g. from cell soma to the periphery in a sensory neuron). Hyperalgesia: exaggerated response to pain. Hypohemia: local (or global) lack of blood in parts of a tissue. Periaquaeductal grey: part of the midbrain, which is -together with other brain regions- important for pain processing, for example descending modulation of pain. Phonophobia: ‘fear of sounds’ – Increased sensitivity to noise. Photophobia: ‘fear of light’ – Increased sensitivity to light, including aversion to well-lit places and daylight. Plasma protein extravasation: the efflux of plasma proteins from a vessel into surrounding tissue. Meningeal nociceptor: sensory receptor which perceives pain signals in the meninges. Scintillation scotoma: scotoma (greek for ‘darkness’) is an area of reduced vision within the visual field. Scintillation scotoma are flashing optical impressions often associated with migraine aura. Trigeminal system: sensory system innervating the head, including the meninges; consists of peripheral and central components (i.e. the trigeminal nerve and specific regions of the midbrain).
Over the last years, neuropeptides and their receptors gained much interest as new treatment options. Various neuropeptides are co-released with classical neurotransmitters (like glutamate) and play important roles for the generation of HYPERALGESIA (see glossary) and pain. Moreover, certain neuropeptides, which modulate neuronal and vascular events, are released during migraine [8]. Therefore, efforts were taken to develop selective ligands to interfere with migraine pain.
Aetiology of migraine Migraine is a complex disorder including neuronal and vascular disturbances. The headache is thought to be started in the central nervous system by the activation of the ‘brainstem migraine generator’, or by cortical spreading depression (CSD). These disturbances then lead to neurogenic vasodilatation within the dura mater. In addition, dural PLASMA PROTEIN EXTRAVASATION (see glossary) is thought to play a role in migraine pathophysiology, although its importance is not clinically proven. Vasodilation and the release of proinflammatory substances in turn lead to sensitization of peripheral and central neurons within the TRIGEMINAL SYSTEM (Fig. 1; see glossary). The current understanding of migraine pathophysiology is repeatedly represented in illustrative reviews [9,10]. All known and experimental treatment options interact with the proposed neuronal or vascular events believed to cause migraine (Table 1). However, the exact mechanism that represents the pivotal step in the aetiology of migraine headache is still unknown, and therefore development of more effective medication remains a difficult task. In the next 328
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sections, the known events leading to migraine headache will be discussed in more detail.
Brainstem migraine generator The impact of brainstem dysfunction for generation of migraine was observed in two pioneering clinical investigations: The first study reported patients with electrode implantation for treatment of chronic pain. In those patients, headache resembling migraine could be observed, when the electrode tip was implanted into the PERIAQUAEDUCTAL GREY (see glossary) region of the brainstem [11]. In addition, a functional magnetic resonance imaging study was performed in migraine patients during spontaneous migraine attacks. Successful treatment of the headache with a triptan reduced the activity in nearly all brain areas that had been activated due to the pain. However, the activation of the brainstem persisted after successful treatment of migraine pain. It is to be assumed that the brainstem has a role as migraine generator that is different from pain processing [12]. The idea of a brainstem ‘migraine generator’ was substantiated using high resolution magnetic resonance technique, as headache patients displayed altered cellular function within brainstem regions associated with pain processing [13]. Interestingly, various neuropeptides which are suggested to play a role in migraine genesis have been localized within the ‘generator region’ [14].
Cortical spreading depression CSD is characterized by a wave of depolarization that spreads over the cortex with a propagation velocity of about 3–5 mm/ min. The depolarization goes along with a short-lasting increase of cerebral blood flow that is followed by a longlasting regional HYPOHEMIA (see glossary). There is strong evidence that CSD is involved in the generation of migraine aura, as reviewed by Sa´nches-del-Rio and Reuter [15]. A typical visual aura is represented by a SCINTILLATION SCOTOMA (see glossary) that starts at the centre of the visual field and slowly propagates to the periphery. The aura is thought to be elicited by propagation of a depolarization wave within the visual cortex. It was calculated that the propagation velocity over the visual cortex is identical to that of the CSD, giving the first evidence for the close relation of CSD and visual aura. The occurrence of CSD during migraine aura was supported by a functional magnetic resonance imaging study: In patients with common migraine, blood oxygenation level-dependent signal changes have been shown that demonstrate at least eight characteristics of CSD, time-locked to the aura. Although there is a body of evidence for CSD being the cause of migraine aura, it is not known if CSD is also present in patients with common migraine. In addition, the influence of CSD on further migraine associated neuronal events is still under debate [16,17].
(A) Standard treatment
(B) Peptides in migraine
(C) Further novel treatment options
Main mechanisms
Therapy against target (examples)
Stage of development
Anti-Inflammation
Inhibition of cox1/2 (NSAIDs)
Meningeal vasoconstriction (+ inhibition of central neuronal sensitization) Anti ‘neurogenic inflammation’
Refs
On market
Standard treatment; inexpensive; but: incomplete pain relief, recurrent headache, etc.
[5]
5-HT1 agonists Triptans; (e.g. sumatriptan) Dihydroergotamines
On market
Standard treatment; but: incomplete pain relief, recurrent headache, etc.
[5,25]
Endothelin-antagonist (Bosentan)
Clinical trial
Actelion http://www.actelion.com/
No clinical efficacy
[36]
NK1-antagonists (GR205171, RPR100893 etc.)
Clinical trials; preclinical
GSKa (http://www.gsk.com/) Sanofi-Aventis (http://www.sanofi-aventis.com/) MSDb, etc.
No clinical efficacy
[39]d
Inhibition of meningeal vasodilation (+ inhibition of central neuronal sensitization)
CGRP-receptor antagonists (BIBN4096BS)
Clinical trial; preclinical
Boehringer Ingelheim (http://www.boehringer-ingelheim.com/) MSD (http://www.msd-uk.co.uk/) BMSc (http://www.bms.com/) Gru¨nenthal (http://www.grunenthal.com/)
Clinical efficacy; no side effects expected
[55]d
Neuronal desensitization (+ inhibition of peptide release)
Somatostatin receptor 2 agonist (Octreotide)
Clinical trial
Novartis (http://www.novartis.com/) GSK (http://www.gsk.com/)
No compelling clinical efficacy at 2 h pain relief
[48]
Neuronal excitability
K+-channel openers (e.g. KCNQ2; for example, BMS-488072)
Preclinical
Elbion (http://www.elbion.de/), BMS
d
Glutamate antagonist (mGlu5, AMPA; Kainate/etc.; ADX-10059, NGX-424, FP-0011)
Phase I/ II
Addex Pharmaceuticals (http://www.addexpharma.com/), Torrey Pines Pharmaceutials (http://www.torreypinestherapeutics.com/), Faust (http://www.faustpharma.com/)
d
EP4-antagonists (PGN-1531; BGC-20-1531)
Preclinical
Astellas (http://www.astellas.com/), BTG (http://www.btgplc.com/),
d
NOS-inhibitors (iNOS/ nNOS; 289013, 274150)
Preclinical; Phase II
GSK (http://www.gsk.com/)
d
TRPV1-blockers (274150)
Phase II
GSK (http://www.gsk.com/)
d
a
GSK: Glaxo Smith Kline. MSD: Merck Sharp & Dome. c BMS: Bristol-Myers Squibb. d Knowledge from pipeline databases, company homepages and press releases. b
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Pros/Cons
Neuronal excitability/ vasoconstriction
Who is working on target
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Table 1. Pharmacological treatment options for migraine headache
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Figure 1. Role of neuropeptides in the pathophysiology of migraine. Migraine is triggered by abnormal activity within the cortex (CSD) or brainstem (‘migraine generator’). Preclinical studies indicated that endothelin and CGRP may play a role in generation and conduction of CSD. The disturbances of the central nervous system leads to antidromic activation of meningeal nociceptors followed by the release of neuropeptides like CGRP and substance P at the peripheral endings of the nociceptors. The peptides trigger dural neurogenic vasodilation, plasma protein extravasation and sensitization of nociceptors that can be modulated by ligands of peptid receptors (mainly CGRP, endothelin, substance P, VIP). Vasodilation and peripheral sensitization in turn is followed by sensitization of the central trigeminal system. While, for example, CGRP reinforces the sensitivity of central neurones it was shown that ligands of the somatostatin receptors desensitize the central neurones. Finally, increased trigeminal sensitivity is felt as headache. Although preclinical studies gave hints to several neuropeptides as players in the migraine pathophysiology, only CGRP antagonism showed clinical efficacy (bold), most probably via inhibition of vasodilatation and central sensitization. In addition, it was suggested that centrally acting somatostatin agonists might be effective in treatment of migraine by desensitization of brainstem neurones (bold).
CSD can at least partially be modulated by neuropeptides: CSD can be elicited by endothelin, whereas the CSD associated dilatation of pial arteries is dependent on CGRP [18,19].
plasma protein extravasation, was not effective in treatment of migraine headache [24].
Peripheral and central sensitization Neurogenic vasodilatation and plasma protein extravasation Meningeal blood vessels are innervated by trigeminal sensory neurons. These neurons send their central projections among others to the trigeminal nucleus caudalis, a relay point for nociceptive processing. MENINGEAL NOCICEPTORS (see glossary) are known to contain vasoactive neuropeptides like substance P and CGRP, which are released by ANTIDROMIC STIMULATION (see glossary) of the trigeminal ganglion [9,20]. There is little doubt that during migraine, the trigeminal nerve becomes activated with subsequent release of neuropeptides at their peripheral nerve endings, as elevated levels of trigeminal peptides are found in jugular blood during the headache phase of migraine [8,21]. In particular, substance P and CGRP are known to lead to plasma protein extravasation and vasodilatation [22]. In animal models neurogenic vascular events are inhibited by migraine medications like ergots and triptans, supporting the hypothesis of neurogenic inflammation in the context of migraine [23]. However, inhibition of plasma protein extravasation alone is not efficient in the treatment of migraine headache, as CP-122,288, a potent inhibitor of neurogenic 330
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It has been suggested that the throbbing type of migraine pain as well as the worsening of the pain after physical activity is associated with increased responsiveness of meningeal nociceptors. In addition, it has been observed that migraine headache is often associated with cutaneous ALLODYNIA (see glossary), pointing to development of central sensitization. Cutaneous allodynia and the throbbing pain may be triggered by neurogenic inflammation of the dura mater, as meningeal inflammation in rat leads to central and peripheral sensitization within the trigeminal nervous system. Interestingly, sumatriptan exhibits higher efficacy in non-allodynic patients. In patients who had already developed central sensitization, the medication seems to be less effective [25]. The identification of mechanisms which will enable migraine headache treatment independent of the state of the central sensitization will be a challenging task.
Neuropeptides in migraine and pain Neuropeptides are often collocated with ‘classical’ low molecular weight neurotransmitters. It is well known that various
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neuropeptides play important roles in development of hyperalgesia and pain within the spinal system [26]. Levels of several neuropeptides like CGRP and vasoactive intestinal peptide (VIP) have shown to be changed during migraine headache [8,27,28]. Together with their ability to modulate neuronal as well as vascular responsiveness, neuropeptides have been ascribed to play important roles in the aetiology of migraine headache. Preclinical studies gave hints to substance P, somatostatin, endothelin and CGRP among other peptides as important players for migraine pathophysiology (Fig. 1). The various neuropeptides are discussed in more detail in the following sub sections. Information about the effects of neuropeptide ligands in clinical migraine trails can be found in Table 1.
Neuropeptide Y (NPY) and vasoactive intestinal peptide Migraine is associated with autonomic symptoms like nausea and diarrhoea. In addition, unilateral autonomic nasal and ocular symptoms have been described during migraine headache [29]. NPY and VIP are two important neuropeptides which are associated with the autonomic nervous system and therefore are thought to play a role for migraine pathophysiology. NPY is collocated within the sympathetic, and VIP within parasympathetic neurons innervating the middle meningeal artery as well as the ‘migraine generator’ region, indicating a possible impact of these peptides on vascular and neuronal mechanisms associated with migraine headache [14,30]. Peripheral blood levels of NPY are unchanged in migraineurs. However, increased levels of VIP are found in saliva during migraine attacks, giving a hint to an imbalance of the parasympathetic- sympathetic tone during migraine [27].
Endothelin Three genetically different endothelins have been described [31]. Endothelin-1 is expressed by a great variety of cell types, including endothelial cells and neurons [32]. This peptide is released during migraine attacks and can induce vasoconstriction, as well as vasodilation via ETA and ETB receptors [33,34]. In addition, it has been shown that endothelin plays a role in mediating the neurogenic plasma extravasation in rat dura mater and potently induces CSD in intact animals [18,35]. Therefore, a role of endothelin-1 in the aetiology of migraine was suggested. Bosentan (Acetlion), a mixed antagonist of ETA and ETB, was shown to block neurogenic plasma extravasation with similar efficacy as sumatriptan. Somewhat surprisingly, the substance was ineffective in aborting migraine attacks in the clinics [35,36]. The inefficacy of Bosentan might be explained by the time course of endothelin release during spontaneous migraine attacks. Plasma levels of endothelin-1 are first increased about 6 h after the beginning of the attack [37]. Bosentan, which
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lacks vasoconstrictor activity, therefore cannot influence the migraine headache before release of the peptide. It may be concluded that endothelin dependent neurogenic plasma extravasation is subordinate, with meningeal vasodilatation and neuronal sensitization playing the pivotal steps in migraine pathogenesis.
Substance P The wide distribution of Substance P throughout the nervous system and its pathophysiological roles are extensively reviewed by Quartara and Maggi [38]. It is known that the peptide plays an important role in spinal pain transmission via activation of the neurokinin-1 receptor (NK-1). Furthermore, substance P antagonists have been suggested for therapy of migraine [39]. The neuropeptide is located within trigeminal ganglion neurons. Stimulation of the ganglion releases the peptide with subsequent activation of NK-1, leading to neurogenic inflammation characterized by vasodilatation and plasma protein extravasation, both suggested to increase meningeal nociception. In turn, noxious meningeal stimulation leads to NK-1 dependent activation of neurons within the brainstem. Because of its impact on neurogenic vascular events in association with increased neuronal activity NK-1 became a highly interesting target for the treatment of migraine. Several NK-1 antagonists (e.g. RPR 100893 and GR205171) have been shown to inhibit migraine associated vascular, or neuronal activity. Consequently, the compounds have been clinically evaluated in acute treatment of migraine. Disappointingly, none of the substances tested were superior to placebo, independent of their ability to cross the blood brain barrier [40,41]. Interestingly, NK-1 antagonists are also ineffective in the treatment of chronic pain in patients [42], and it has to be assumed that the impact of substance P for the development of pain in humans has been overestimated.
Somatostatin Receptors for somatostatin are widely distributed within central neurons associated with pain processing. The peptide is known to desensitize pain relevant central neurons [43,44]. A recent clinical study reported decreased somatostatin levels within the cerebrospinal fluid in migraine patients [45], highlighting the importance of centrally available somatostatin for suppression of migraine. In addition, somatostatin receptors are located within peripheral trigeminal ganglion neurons [46]. Application of somatostatin inhibits neurogenic meningeal vasodilatation via inhibition of CGRP-release from trigeminal ganglion derived nociceptors [47]. Therefore, somatostatin is suggested to play a role in peripheral as well as central mechanisms during migraine pathogenesis. Consequently, somatostatin receptor ligands have been proposed as new targets for the acute treatment of migraine www.drugdiscoverytoday.com
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headache [48]. Octreotide (a somatostatin receptor agonist), however, exhibited no convincing superiority over placebo. Despite these findings, the somatostatin receptor remains an attractive pharmacological approach to primary headache management as efficacy was shown in the treatment of cluster headache. If central sensitization plays a superior role in migraine pathophysiology, somatostatin analogues with good brain penetration might be effective in the treatment of migraine headache.
CGRP Today, development of CGRP receptor antagonist is among the most promising new targets as treatment option of migraine headache [49,50]. It is well known that CGRP levels are increased during migraine headache, most probably due to activation of the afferent trigeminal neurons. Successful treatment of migraine with sumatriptan leads to normalization of CGRP levels [27]. In turn, patients infused with this potent vasodilatatory neuropeptide develop a delayed headache fulfilling the criteria of migraine, indicating a causative role of CGRP in migraine headache [51]. Preclinical studies with Olcegepant (BIBN4096BS; Boehringer-Ingelheim), a non-peptide CGRP antagonist, showed high efficacy in inhibiting neurogenic vasodilatation with no effect on basal blood pressure or heart rate [52]. In addition, the substance was effective in reducing neuronal excitability within the trigeminal nucleus caudalis [53,54]. Consequently, a pioneering clinical proof of concept study was performed to explore the efficacy of BIBN4096BS for treatment of migraine headache [55]. The substance exhibited significant superiority over placebo with respect to responses rate and pain-free rate at 2 h. The rate of recurrence of headache and accompanying symptoms like nausea and photophobia also improved. This clinical trial highlights the importance of CGRP for the generation of migraine headache. Blocking of CGRP receptors represents a novel and attractive target for acute treatment of migraine.
Summary and conclusions Migraine is an episodic disabling headache disorder with a prevalence of about 10% throughout the population, with women being three times more frequently affected than men. Migraine dependent reduced productivity and direct medical costs lead to great economic impact of the disease. Migraine is best understood as a neurovascular disorder. The headache is thought to be started by temporal cortical or brainstem dysfunction. The neuronal disturbances lead to vasodilatation and release of pro-algesic substances within the dura mater which in turn sensitize peripheral and central neurons. Many neurons are able to co-release neuropeptides together with classical transmitters. Several neuropeptides 332
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are known to modulate vascular as well as neuronal responsiveness. The impact of neuropeptides on migraine seems to be obvious, as both neuronal and vascular events play a pivotal role in the aetiology of migraine. Preclinical studies implied substance P, somatostatin, VIP, endothelin antagonists and CGRP as important players for migraine pathophysiology. Although several clinical trials with ligands of neuropeptide receptors have been conducted, only blocking CGRP receptors has shown to be highly effective in the treatment of migraine headache. Clinical and preclinical results point to the leading role of CGRP in the aetiology of migraine through its ability to modulate vascular as well as neuronal activity. Our knowledge of the pathophysiology of migraine largely developed over the last years, and new treatment options have come into reach. Nevertheless, there are outstanding issues still to be resolved to understand more thoroughly this disease.
Outstanding issues Does cortical spreading depression play a role in migraine without aura? How do neuropeptides affect peripheral and central neuronal sensitization? Why did substance P receptor (NK-1) antagonists fail in the clinics for the treatment of migraine and pain? What makes CGRP unique concerning migraine, compared to other neuropeptides?
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Brandli, P. et al. (1996) Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater. Pain 64, 315–322 May, A. et al. (1996) Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 67, 375–378 Hasselblatt, M. et al. (1999) Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine. Neuroreport 10, 423–425 Quartara, L. and Maggi, C.A. (1998) The tachykinin NK1 receptor. Part II: Distribution and pathophysiological roles. Neuropeptides 32, 1–49 May, A. and Goadsby, P.J. (2001) Substance P receptor antagonists in the therapy of migraine. Expert Opin. Investig. Drugs 10, 673–678 Diener, H.C. (2003) RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23, 183–185 Connor, H.E. et al. (1998) Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treatment of migraine. Cephalalgia 18, 392 Hill, R. (2000) NK1 (substance P) receptor antagonists – why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244–246 Schindler, M. et al. (1998) Identification of somatostatin sst2(a) receptor expressing neurones in central regions involved in nociception. Brain Res. 798, 25–35 Helmchen, C. et al. (1995) Inhibition of spinal nociceptive neurons by microinjections of somatostatin into the nucleus raphe magnus and the midbrain periaqueductal gray of the anesthetized cat. Neurosci. Lett. 187, 137–141 Sarchielli, P. et al. (2006) Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia. Cephalalgia 26, 409–415 Ichikawa, H. et al. (2003) The somatostatin SST2A receptor in the rat trigeminal ganglion. Neuroscience 120, 807–813 Pawlak, M. et al. (1999) Somatostatin reduces the meningeal arterial blood flow in the rat. Neuroscience Letters 276, 33–36 Goadsby, P.J. (2005) New targets in the acute treatment of headache. Curr. Opin. Neurol. 18, 283–288 Geppetti, P. et al. (2005) CGRP and migraine: neurogenic inflammation revisited. J. Headache Pain 6, 61–70 Goadsby, P.J. (2005) Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches. Drugs 65, 2557–2567 Lassen, L.H. et al. (2002) CGRP may play a causative role in migraine. Cephalalgia 22, 54–61 Doods, H. et al. (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol. 129, 420–423 Storer, R.J. et al. (2004) Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br. J. Pharmacol. 142, 1171–1181 Fischer, M.J.M. et al. (2005) The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus. J. Neurosci. 25, 5877–5883 Olesen, J. et al. (2004) Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. N. Engl. J. Med. 350, 1104–1110
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Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Pain MECHANISMS
Pathophysiology of migraine: A role for neuropeptides Stefan Just*, Kirsten Arndt, Thomas Weiser, Henri Doods CNS Research, Boehringer Ingelheim Pharma KG, 88397 Biberach an der Riss, Germany
Migraine is a common debilitating neurovascular disorder. Because of their dual role in modulating neuronal and vascular events, neuropeptides have been
Section Editors: Frank Porreca – University of Arizona, Tucson, USA Michael Ossipov – University of Arizona, Tucson, USA
implied to be of importance in migraine pathophysiology. Most clinical trials investigating neuropeptide receptor ligands for the treatment of migraine, however, did not show the desired results. The only exception so far is Olcegepant (BIBN4096BS), a potent and selective antagonist of the calcitonin gene related peptide (CGRP) receptor. In a clinical study, this compound proved to be effective in treating migraine headache, highlighting the essential role of CGRP for pathophysiology of migraine.
Introduction Migraine is a common episodic headache disorder. The disease can be divided into two major sub-types, namely common migraine and migraine with aura. The common migraine is defined as a recurrent, unilateral headache disorder manifesting in attacks lasting 4–72 h. The pain is of pulsating quality, moderate to severe intensity and associated with nausea and/or PHOTOPHOBIA and PHONOPHOBIA (see glossary) [1]. Migraine with aura is characterized by a headache with features of the common migraine with reversible focal neurological symptoms (like scintillation scotoma; see glossary) that develop before the headache and last up to 60 min [1]. Within Europe and the Americas approximately 6–8% of men and 15–22% of women suffer from migraine, with *Corresponding author: S. Just ([email protected]) 1740-6765/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2006.07.002
women being three times more frequently affected than men. In both sexes, the prevalence peaks at about 40 years of age. Migraine headache leads to high indirect costs because of reduced productivity and due to absenteeism. In addition, annual direct medical costs for migraine care are about $ 1 billion in the USA. Therefore, the impact of migraine on healthcare resource utilization and work loss is very high [2,3]. Currently, mild migraine attacks are most frequently treated with analgesics like nonsteroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are treated with ergots or specific 5HT1B/D agonists, the so-called triptans (named after the first compound with this mechanism of action, sumatriptan (Glaxo Smith Kline); see Table 1) [4]. An important recent clinical trial has shown that sumatriptan was only slightly more effective than an NSAIDs in reducing migraine pain [5]. The main drawbacks of all current treatment options are latency until improvement of headache, incomplete and inconsistent pain relief, as well as recurrence of headache. Furthermore, the medications exhibit the risk of cardiovascular or intestinal side effects [6]. Therefore, there is still much room for improvement of abortive migraine treatment. Medications for the prophylaxis of migraine are available, but such drugs (e.g. topiramate) cause unwanted effects and only reduce the number of migraine attacks without suppressing migraine completely [7]. To overcome these drawbacks, novel treatment options would be desirable. 327
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Glossary Allodynia: exaggerated response to otherwise non-noxious stimuli. Migraine is often associated with thermal and mechanical hyperresponsiveness within the periorbital region. Antidromic stimulation: stimulation of a nerve fibre which induces action potential propagation opposite to the normal direction (e. g. from cell soma to the periphery in a sensory neuron). Hyperalgesia: exaggerated response to pain. Hypohemia: local (or global) lack of blood in parts of a tissue. Periaquaeductal grey: part of the midbrain, which is -together with other brain regions- important for pain processing, for example descending modulation of pain. Phonophobia: ‘fear of sounds’ – Increased sensitivity to noise. Photophobia: ‘fear of light’ – Increased sensitivity to light, including aversion to well-lit places and daylight. Plasma protein extravasation: the efflux of plasma proteins from a vessel into surrounding tissue. Meningeal nociceptor: sensory receptor which perceives pain signals in the meninges. Scintillation scotoma: scotoma (greek for ‘darkness’) is an area of reduced vision within the visual field. Scintillation scotoma are flashing optical impressions often associated with migraine aura. Trigeminal system: sensory system innervating the head, including the meninges; consists of peripheral and central components (i.e. the trigeminal nerve and specific regions of the midbrain).
Over the last years, neuropeptides and their receptors gained much interest as new treatment options. Various neuropeptides are co-released with classical neurotransmitters (like glutamate) and play important roles for the generation of HYPERALGESIA (see glossary) and pain. Moreover, certain neuropeptides, which modulate neuronal and vascular events, are released during migraine [8]. Therefore, efforts were taken to develop selective ligands to interfere with migraine pain.
Aetiology of migraine Migraine is a complex disorder including neuronal and vascular disturbances. The headache is thought to be started in the central nervous system by the activation of the ‘brainstem migraine generator’, or by cortical spreading depression (CSD). These disturbances then lead to neurogenic vasodilatation within the dura mater. In addition, dural PLASMA PROTEIN EXTRAVASATION (see glossary) is thought to play a role in migraine pathophysiology, although its importance is not clinically proven. Vasodilation and the release of proinflammatory substances in turn lead to sensitization of peripheral and central neurons within the TRIGEMINAL SYSTEM (Fig. 1; see glossary). The current understanding of migraine pathophysiology is repeatedly represented in illustrative reviews [9,10]. All known and experimental treatment options interact with the proposed neuronal or vascular events believed to cause migraine (Table 1). However, the exact mechanism that represents the pivotal step in the aetiology of migraine headache is still unknown, and therefore development of more effective medication remains a difficult task. In the next 328
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sections, the known events leading to migraine headache will be discussed in more detail.
Brainstem migraine generator The impact of brainstem dysfunction for generation of migraine was observed in two pioneering clinical investigations: The first study reported patients with electrode implantation for treatment of chronic pain. In those patients, headache resembling migraine could be observed, when the electrode tip was implanted into the PERIAQUAEDUCTAL GREY (see glossary) region of the brainstem [11]. In addition, a functional magnetic resonance imaging study was performed in migraine patients during spontaneous migraine attacks. Successful treatment of the headache with a triptan reduced the activity in nearly all brain areas that had been activated due to the pain. However, the activation of the brainstem persisted after successful treatment of migraine pain. It is to be assumed that the brainstem has a role as migraine generator that is different from pain processing [12]. The idea of a brainstem ‘migraine generator’ was substantiated using high resolution magnetic resonance technique, as headache patients displayed altered cellular function within brainstem regions associated with pain processing [13]. Interestingly, various neuropeptides which are suggested to play a role in migraine genesis have been localized within the ‘generator region’ [14].
Cortical spreading depression CSD is characterized by a wave of depolarization that spreads over the cortex with a propagation velocity of about 3–5 mm/ min. The depolarization goes along with a short-lasting increase of cerebral blood flow that is followed by a longlasting regional HYPOHEMIA (see glossary). There is strong evidence that CSD is involved in the generation of migraine aura, as reviewed by Sa´nches-del-Rio and Reuter [15]. A typical visual aura is represented by a SCINTILLATION SCOTOMA (see glossary) that starts at the centre of the visual field and slowly propagates to the periphery. The aura is thought to be elicited by propagation of a depolarization wave within the visual cortex. It was calculated that the propagation velocity over the visual cortex is identical to that of the CSD, giving the first evidence for the close relation of CSD and visual aura. The occurrence of CSD during migraine aura was supported by a functional magnetic resonance imaging study: In patients with common migraine, blood oxygenation level-dependent signal changes have been shown that demonstrate at least eight characteristics of CSD, time-locked to the aura. Although there is a body of evidence for CSD being the cause of migraine aura, it is not known if CSD is also present in patients with common migraine. In addition, the influence of CSD on further migraine associated neuronal events is still under debate [16,17].
(A) Standard treatment
(B) Peptides in migraine
(C) Further novel treatment options
Main mechanisms
Therapy against target (examples)
Stage of development
Anti-Inflammation
Inhibition of cox1/2 (NSAIDs)
Meningeal vasoconstriction (+ inhibition of central neuronal sensitization) Anti ‘neurogenic inflammation’
Refs
On market
Standard treatment; inexpensive; but: incomplete pain relief, recurrent headache, etc.
[5]
5-HT1 agonists Triptans; (e.g. sumatriptan) Dihydroergotamines
On market
Standard treatment; but: incomplete pain relief, recurrent headache, etc.
[5,25]
Endothelin-antagonist (Bosentan)
Clinical trial
Actelion http://www.actelion.com/
No clinical efficacy
[36]
NK1-antagonists (GR205171, RPR100893 etc.)
Clinical trials; preclinical
GSKa (http://www.gsk.com/) Sanofi-Aventis (http://www.sanofi-aventis.com/) MSDb, etc.
No clinical efficacy
[39]d
Inhibition of meningeal vasodilation (+ inhibition of central neuronal sensitization)
CGRP-receptor antagonists (BIBN4096BS)
Clinical trial; preclinical
Boehringer Ingelheim (http://www.boehringer-ingelheim.com/) MSD (http://www.msd-uk.co.uk/) BMSc (http://www.bms.com/) Gru¨nenthal (http://www.grunenthal.com/)
Clinical efficacy; no side effects expected
[55]d
Neuronal desensitization (+ inhibition of peptide release)
Somatostatin receptor 2 agonist (Octreotide)
Clinical trial
Novartis (http://www.novartis.com/) GSK (http://www.gsk.com/)
No compelling clinical efficacy at 2 h pain relief
[48]
Neuronal excitability
K+-channel openers (e.g. KCNQ2; for example, BMS-488072)
Preclinical
Elbion (http://www.elbion.de/), BMS
d
Glutamate antagonist (mGlu5, AMPA; Kainate/etc.; ADX-10059, NGX-424, FP-0011)
Phase I/ II
Addex Pharmaceuticals (http://www.addexpharma.com/), Torrey Pines Pharmaceutials (http://www.torreypinestherapeutics.com/), Faust (http://www.faustpharma.com/)
d
EP4-antagonists (PGN-1531; BGC-20-1531)
Preclinical
Astellas (http://www.astellas.com/), BTG (http://www.btgplc.com/),
d
NOS-inhibitors (iNOS/ nNOS; 289013, 274150)
Preclinical; Phase II
GSK (http://www.gsk.com/)
d
TRPV1-blockers (274150)
Phase II
GSK (http://www.gsk.com/)
d
a
GSK: Glaxo Smith Kline. MSD: Merck Sharp & Dome. c BMS: Bristol-Myers Squibb. d Knowledge from pipeline databases, company homepages and press releases. b
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Pros/Cons
Neuronal excitability/ vasoconstriction
Who is working on target
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Table 1. Pharmacological treatment options for migraine headache
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Figure 1. Role of neuropeptides in the pathophysiology of migraine. Migraine is triggered by abnormal activity within the cortex (CSD) or brainstem (‘migraine generator’). Preclinical studies indicated that endothelin and CGRP may play a role in generation and conduction of CSD. The disturbances of the central nervous system leads to antidromic activation of meningeal nociceptors followed by the release of neuropeptides like CGRP and substance P at the peripheral endings of the nociceptors. The peptides trigger dural neurogenic vasodilation, plasma protein extravasation and sensitization of nociceptors that can be modulated by ligands of peptid receptors (mainly CGRP, endothelin, substance P, VIP). Vasodilation and peripheral sensitization in turn is followed by sensitization of the central trigeminal system. While, for example, CGRP reinforces the sensitivity of central neurones it was shown that ligands of the somatostatin receptors desensitize the central neurones. Finally, increased trigeminal sensitivity is felt as headache. Although preclinical studies gave hints to several neuropeptides as players in the migraine pathophysiology, only CGRP antagonism showed clinical efficacy (bold), most probably via inhibition of vasodilatation and central sensitization. In addition, it was suggested that centrally acting somatostatin agonists might be effective in treatment of migraine by desensitization of brainstem neurones (bold).
CSD can at least partially be modulated by neuropeptides: CSD can be elicited by endothelin, whereas the CSD associated dilatation of pial arteries is dependent on CGRP [18,19].
plasma protein extravasation, was not effective in treatment of migraine headache [24].
Peripheral and central sensitization Neurogenic vasodilatation and plasma protein extravasation Meningeal blood vessels are innervated by trigeminal sensory neurons. These neurons send their central projections among others to the trigeminal nucleus caudalis, a relay point for nociceptive processing. MENINGEAL NOCICEPTORS (see glossary) are known to contain vasoactive neuropeptides like substance P and CGRP, which are released by ANTIDROMIC STIMULATION (see glossary) of the trigeminal ganglion [9,20]. There is little doubt that during migraine, the trigeminal nerve becomes activated with subsequent release of neuropeptides at their peripheral nerve endings, as elevated levels of trigeminal peptides are found in jugular blood during the headache phase of migraine [8,21]. In particular, substance P and CGRP are known to lead to plasma protein extravasation and vasodilatation [22]. In animal models neurogenic vascular events are inhibited by migraine medications like ergots and triptans, supporting the hypothesis of neurogenic inflammation in the context of migraine [23]. However, inhibition of plasma protein extravasation alone is not efficient in the treatment of migraine headache, as CP-122,288, a potent inhibitor of neurogenic 330
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It has been suggested that the throbbing type of migraine pain as well as the worsening of the pain after physical activity is associated with increased responsiveness of meningeal nociceptors. In addition, it has been observed that migraine headache is often associated with cutaneous ALLODYNIA (see glossary), pointing to development of central sensitization. Cutaneous allodynia and the throbbing pain may be triggered by neurogenic inflammation of the dura mater, as meningeal inflammation in rat leads to central and peripheral sensitization within the trigeminal nervous system. Interestingly, sumatriptan exhibits higher efficacy in non-allodynic patients. In patients who had already developed central sensitization, the medication seems to be less effective [25]. The identification of mechanisms which will enable migraine headache treatment independent of the state of the central sensitization will be a challenging task.
Neuropeptides in migraine and pain Neuropeptides are often collocated with ‘classical’ low molecular weight neurotransmitters. It is well known that various
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neuropeptides play important roles in development of hyperalgesia and pain within the spinal system [26]. Levels of several neuropeptides like CGRP and vasoactive intestinal peptide (VIP) have shown to be changed during migraine headache [8,27,28]. Together with their ability to modulate neuronal as well as vascular responsiveness, neuropeptides have been ascribed to play important roles in the aetiology of migraine headache. Preclinical studies gave hints to substance P, somatostatin, endothelin and CGRP among other peptides as important players for migraine pathophysiology (Fig. 1). The various neuropeptides are discussed in more detail in the following sub sections. Information about the effects of neuropeptide ligands in clinical migraine trails can be found in Table 1.
Neuropeptide Y (NPY) and vasoactive intestinal peptide Migraine is associated with autonomic symptoms like nausea and diarrhoea. In addition, unilateral autonomic nasal and ocular symptoms have been described during migraine headache [29]. NPY and VIP are two important neuropeptides which are associated with the autonomic nervous system and therefore are thought to play a role for migraine pathophysiology. NPY is collocated within the sympathetic, and VIP within parasympathetic neurons innervating the middle meningeal artery as well as the ‘migraine generator’ region, indicating a possible impact of these peptides on vascular and neuronal mechanisms associated with migraine headache [14,30]. Peripheral blood levels of NPY are unchanged in migraineurs. However, increased levels of VIP are found in saliva during migraine attacks, giving a hint to an imbalance of the parasympathetic- sympathetic tone during migraine [27].
Endothelin Three genetically different endothelins have been described [31]. Endothelin-1 is expressed by a great variety of cell types, including endothelial cells and neurons [32]. This peptide is released during migraine attacks and can induce vasoconstriction, as well as vasodilation via ETA and ETB receptors [33,34]. In addition, it has been shown that endothelin plays a role in mediating the neurogenic plasma extravasation in rat dura mater and potently induces CSD in intact animals [18,35]. Therefore, a role of endothelin-1 in the aetiology of migraine was suggested. Bosentan (Acetlion), a mixed antagonist of ETA and ETB, was shown to block neurogenic plasma extravasation with similar efficacy as sumatriptan. Somewhat surprisingly, the substance was ineffective in aborting migraine attacks in the clinics [35,36]. The inefficacy of Bosentan might be explained by the time course of endothelin release during spontaneous migraine attacks. Plasma levels of endothelin-1 are first increased about 6 h after the beginning of the attack [37]. Bosentan, which
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lacks vasoconstrictor activity, therefore cannot influence the migraine headache before release of the peptide. It may be concluded that endothelin dependent neurogenic plasma extravasation is subordinate, with meningeal vasodilatation and neuronal sensitization playing the pivotal steps in migraine pathogenesis.
Substance P The wide distribution of Substance P throughout the nervous system and its pathophysiological roles are extensively reviewed by Quartara and Maggi [38]. It is known that the peptide plays an important role in spinal pain transmission via activation of the neurokinin-1 receptor (NK-1). Furthermore, substance P antagonists have been suggested for therapy of migraine [39]. The neuropeptide is located within trigeminal ganglion neurons. Stimulation of the ganglion releases the peptide with subsequent activation of NK-1, leading to neurogenic inflammation characterized by vasodilatation and plasma protein extravasation, both suggested to increase meningeal nociception. In turn, noxious meningeal stimulation leads to NK-1 dependent activation of neurons within the brainstem. Because of its impact on neurogenic vascular events in association with increased neuronal activity NK-1 became a highly interesting target for the treatment of migraine. Several NK-1 antagonists (e.g. RPR 100893 and GR205171) have been shown to inhibit migraine associated vascular, or neuronal activity. Consequently, the compounds have been clinically evaluated in acute treatment of migraine. Disappointingly, none of the substances tested were superior to placebo, independent of their ability to cross the blood brain barrier [40,41]. Interestingly, NK-1 antagonists are also ineffective in the treatment of chronic pain in patients [42], and it has to be assumed that the impact of substance P for the development of pain in humans has been overestimated.
Somatostatin Receptors for somatostatin are widely distributed within central neurons associated with pain processing. The peptide is known to desensitize pain relevant central neurons [43,44]. A recent clinical study reported decreased somatostatin levels within the cerebrospinal fluid in migraine patients [45], highlighting the importance of centrally available somatostatin for suppression of migraine. In addition, somatostatin receptors are located within peripheral trigeminal ganglion neurons [46]. Application of somatostatin inhibits neurogenic meningeal vasodilatation via inhibition of CGRP-release from trigeminal ganglion derived nociceptors [47]. Therefore, somatostatin is suggested to play a role in peripheral as well as central mechanisms during migraine pathogenesis. Consequently, somatostatin receptor ligands have been proposed as new targets for the acute treatment of migraine www.drugdiscoverytoday.com
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headache [48]. Octreotide (a somatostatin receptor agonist), however, exhibited no convincing superiority over placebo. Despite these findings, the somatostatin receptor remains an attractive pharmacological approach to primary headache management as efficacy was shown in the treatment of cluster headache. If central sensitization plays a superior role in migraine pathophysiology, somatostatin analogues with good brain penetration might be effective in the treatment of migraine headache.
CGRP Today, development of CGRP receptor antagonist is among the most promising new targets as treatment option of migraine headache [49,50]. It is well known that CGRP levels are increased during migraine headache, most probably due to activation of the afferent trigeminal neurons. Successful treatment of migraine with sumatriptan leads to normalization of CGRP levels [27]. In turn, patients infused with this potent vasodilatatory neuropeptide develop a delayed headache fulfilling the criteria of migraine, indicating a causative role of CGRP in migraine headache [51]. Preclinical studies with Olcegepant (BIBN4096BS; Boehringer-Ingelheim), a non-peptide CGRP antagonist, showed high efficacy in inhibiting neurogenic vasodilatation with no effect on basal blood pressure or heart rate [52]. In addition, the substance was effective in reducing neuronal excitability within the trigeminal nucleus caudalis [53,54]. Consequently, a pioneering clinical proof of concept study was performed to explore the efficacy of BIBN4096BS for treatment of migraine headache [55]. The substance exhibited significant superiority over placebo with respect to responses rate and pain-free rate at 2 h. The rate of recurrence of headache and accompanying symptoms like nausea and photophobia also improved. This clinical trial highlights the importance of CGRP for the generation of migraine headache. Blocking of CGRP receptors represents a novel and attractive target for acute treatment of migraine.
Summary and conclusions Migraine is an episodic disabling headache disorder with a prevalence of about 10% throughout the population, with women being three times more frequently affected than men. Migraine dependent reduced productivity and direct medical costs lead to great economic impact of the disease. Migraine is best understood as a neurovascular disorder. The headache is thought to be started by temporal cortical or brainstem dysfunction. The neuronal disturbances lead to vasodilatation and release of pro-algesic substances within the dura mater which in turn sensitize peripheral and central neurons. Many neurons are able to co-release neuropeptides together with classical transmitters. Several neuropeptides 332
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are known to modulate vascular as well as neuronal responsiveness. The impact of neuropeptides on migraine seems to be obvious, as both neuronal and vascular events play a pivotal role in the aetiology of migraine. Preclinical studies implied substance P, somatostatin, VIP, endothelin antagonists and CGRP as important players for migraine pathophysiology. Although several clinical trials with ligands of neuropeptide receptors have been conducted, only blocking CGRP receptors has shown to be highly effective in the treatment of migraine headache. Clinical and preclinical results point to the leading role of CGRP in the aetiology of migraine through its ability to modulate vascular as well as neuronal activity. Our knowledge of the pathophysiology of migraine largely developed over the last years, and new treatment options have come into reach. Nevertheless, there are outstanding issues still to be resolved to understand more thoroughly this disease.
Outstanding issues Does cortical spreading depression play a role in migraine without aura? How do neuropeptides affect peripheral and central neuronal sensitization? Why did substance P receptor (NK-1) antagonists fail in the clinics for the treatment of migraine and pain? What makes CGRP unique concerning migraine, compared to other neuropeptides?
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