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Recent advances in understanding migraine mechanisms, molecules and therapeutics
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TRENDS in Molecular Medicine
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Recent advances in understanding migraine mechanisms, molecules and therapeutics Peter J. Goadsby Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK WC1N 3BG
Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca2+ channel), ATP1A2 (N+–K+-ATPase) and SCN1A (Na+ channel) genes. Physiological studies in humans and studies of the experimental correlate – cortical spreading depression (CSD) – provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulation – a system failure of normal sensory processing. Introduction Migraine is an episodic brain disorder that affects 15% of the population [1]; it can be highly disabling, and has been estimated to be the most costly neurological disorder in the European Community at >s27 billion per year [2]. Migraine is a familial episodic disorder, the key marker of which is headache with certain associated features (Table 1). By studying its component parts, one can gain insights into potential molecular mechanisms that might direct the development of new therapies. For a more-general clinical account of the disorder and its treatments, texts are available [3–5]. Here, I consider the known pathophysiology of migraine and attempt to integrate the molecular mechanisms that are emerging. It must be said that the molecular basis of migraine is not understood yet, although one can infer much from what is known of the pathophysiology and its treatment. The elements to be considered are: (i) genetics of migraine; (ii) physiological basis of the aura; (iii) Corresponding author: Goadsby, P.J. ([email protected]). Available online 1 December 2006. www.sciencedirect.com
physiology and pharmacology of the pain-producing innervation of the dura mater and cranial vessels – the trigeminovascular system; and (iv) brainstem and diencephalic modulatory systems that influence trigeminal pain transmission and other sensory modality processing. Migraine is a form of sensory processing disturbance with wide ramifications within the CNS. Although pain pathways are used as an example, it is important to remember that migraine is a complex disorder for which a unitary molecular explanation seems a long way off. Animal models of the constituent parts of the disorder have been useful in dissecting some of the mechanisms, although each of them has its limitations [6]. Genetics of migraine One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder. It is clear from clinical practice that many patients have firstdegree relatives who also suffer from migraine [4,7]. Transmission of migraine from parents to children has been reported as early as the seventeenth century, and numerous published studies have described a positive family history [3]. Identification of the genes that are responsible for the inherited component has been fruitful in beginning to point to particular molecular mechanisms of the disorder. This work has taken advantage of the clear inherited aura phenotype of familial hemiplegic migraine (FHM) to suggest that migraine aura has a crucial ionopathic component [8]. Familial hemiplegic migraine (FHM) The biological basis for the linkage of FHM to chromosome 19p13 is the presence of mutations [9] in the Cav2.1 (P/Q) type voltage-gated Ca2+ channel gene (CACNA1A). Now known as FHM-I, this mutation is responsible for 50% of identified FHM families. One consequence of this mutation is enhanced glutamate release. Mutations in the ATP1A2 gene (also known as FHM-II) [10] are responsible for 20% of FHM families. The ATP1A2 gene encodes a Na+–K+ ATPase and the mutation results in a smaller electrochemical gradient for Na+. One effect of this is to reduce or inactivate astrocytic glutamate transporters, leading to a build-up of synaptic glutamate. Interestingly, the phenotype of some FHM-II patients involves epilepsy. Recently, FHM-III has been identified as a mutation in a Na+ channel gene (SCN1A) [11]. FHM-III would facilitate repetitive
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Table 1. International Headache Society features of migraine [18] Repeated episodic headache (4–72 hrs) with the following features: Any one of: Any two of: Nausea and/or vomiting Unilateral Photophobia and phonophobia Throbbing Worsened by movement Moderate or severe
high-frequency discharges that might also increase synaptic glutamate levels. The consequence of all these mutations has been considered and debated [12]. Linking channel disturbances for the first time to the aura process has shown that human mutations that are expressed in a knock-in mouse produce a reduced threshold for cortical spreading depression (CSD) [13], which has profound implications for understanding migraine aura [14]. These mutations seem to produce a net gain-of-function effect because the cortex becomes more susceptible to stimuli that trigger CSD, although this is not universally accepted [15]. CSD is widely considered to be at the basis for migraine aura [16], and the convergence of each FHM mutation to increase synaptic glutamate is an attractive way to conceptualise how CSD might be more-easily triggered in FHM patients [17]. Migraine aura Migraine aura is defined as a focal neurological disturbance that manifests itself as visual, sensory or motor symptoms [18]. It is observed in 30% of migraine patients [19], and it is clearly neurally driven [16]. The hypothesis that the aura is the human equivalent of CSD of Leao [20] has been well established [16]. Observations of human patients have suggested that human aura has its equivalent in animals CSD [21]. An area of controversy surrounds whether aura triggers the rest of the attack and is painful [17]. Based on the available experimental and clinical data, Goadsby [22] is not at all convinced that aura is painful, but this does not diminish its interest or the importance of understanding it. Indeed, therapeutic developments might shed more light on the relationship between aura and headache, and on the molecular basis for aura. Tonabersat (SB-220453) is an inhibitor of CSD that has entered clinical trials of migraine. Tonabersat inhibits CSD, CSD-induced nitric-oxide (NO) release and cerebral vasodilation [23]. Tonabersat does not constrict isolated human blood vessels [24], but inhibits trigeminally induced craniovascular effects [25]. Remarkably, topiramate, a proven preventive agent in migraine [26], also inhibits CSD in cats and rats [27]. Topiramate inhibits trigeminal neurons that are activated by nociceptive intracranial afferents [28], but not by a local trigeminal mechanism [29]. Ayata et al. [30] have attempted to correlate the preventive action of a range of medicines with an effect on CSD. These authors studied topiramate, valproate, amitriptyline, propranolol and methysergide. Topiramate, valproate and amitriptyline inhibited CSD induction at doses that are typically used in rodent studies, none of which was similar to the dose that is used in migraine www.sciencedirect.com
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prevention. The dose of propranolol used was four times that reported in previous rat studies [31], whereas methysergide had no effect on speed of propagation [30]. CSD inhibition might be a model system for the study of migraine to help developing preventive medicines, although this seems far from clearly established. Headache pathophysiology Peripheral mechanisms Throbbing pain is a classical and frequent, although not invariable, clinical manifestation of migraine. It has been therefore suggested that cranial vessels, their innervation or the control mechanisms that gate input from these structures have a role in this disorder. The dura mater is innervated by branches of the first (ophthalmic) division of the trigeminal nerve. Stimulation of the trigeminal ganglion results in plasma protein extravasation (PPE) in the dura mater [32], cerebral vasodilation [33] and local nerve stimulation in dural vasodilation [34]. PPE has two important components: vasodilation and leakage of plasma proteins. The extravasation component relies on the substance P (neurokinin-1) receptor [35], which is highly effective in blocking dural PPE [36]. CSD can activate trigeminal neurons in the rat [37] and matrix metalloproteinase (MMP)-9, which leads to increased vascular permeability [38]. Repeated attacks on membrane integrity by MMPs seem an implausible scenario in a disorder, the natural course of which is to remit [1]. Moreover, it is clear from clinical studies [39] that neurokinin-1 antagonists are not effective in migraine and, indeed, there is no direct convincing evidence for the role of dural PPE in human migraine [40]. Sensitisation and migraine Although it is highly improbable that there is a significant sterile inflammatory response in the dura mater during migraine, it is clear that a form of sensitisation takes place during migraine, because allodynia – pain from non-noxious stimuli – is common. About two-thirds of migraine patients complain of allodynia [41]. It has been suggested in an open-label study that triptan effects might be predicted by the presence or absence of allodynia, where its presence indicates a poor clinical response [42]. However, results from a placebo-controlled double-blind study suggest that allodynia, at least as reflected by sensitivity to cutaneous inputs, is not predictive of headache relief by a triptan in acute migraine [43]. Particularly interesting is the demonstration of allodynia in the upper limbs that are ipsilateral and contralateral to the pain. This finding is consistent with at least third-order neuronal sensitisation, such as sensitisation of thalamic neurons, placing the pathophysiology of this manifestation within the CNS. Sensitisation in migraine might be peripheral with local release of inflammatory markers that would activate trigeminal nociceptors [44]. More probable in migraine is a form of central sensitisation, which might be classic central sensitisation [45], or a form of disinhibitory sensitisation with dysfunction of descending modulatory pathways [46]. Just as dihydroergotamine (DHE) can block trigeminovascular nociceptive transmission [47], probably by a local effect in the trigeminocervical complex [48], DHE can
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block central sensitisation that is associated with dural stimulation by an ‘inflammatory soup’ [49]. Interestingly, aspirin is also effective in blocking second-order trigeminovascular neurons [50], and cyclooxygenase mechanisms might be important in allodynia [51]. Such observations are already being translated in clinical development through trials of combined triptan–non steroidal antiinflammatory drug (NSAID) combination medicines that might offer a therapeutic advantage in terms of headache recurrence. Neuropeptide release and migraine Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both calcitonin gene-related peptide (CGRP) and substance P (SP) [52]. In the cat, trigeminal ganglion stimulation also increases cerebral blood flow by a pathway traversing the greater superficial petrosal branch of the facial nerve [33], releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP) [53]. Stimulation of the more-specifically vascular painproducing superior sagittal sinus increases cerebral blood flow and jugular vein CGRP levels. Evidence from humans that CGRP level is elevated in the headache phase of migraine [54,55], cluster headache [56,57] and chronic paroxysmal hemicrania [58] supports the view that the trigeminovascular system might be activated for a protective role in these conditions. Moreover, NO-donor-triggered migraine, which is the typical form of migraine [59], also results in increased levels of CGRP [60] that are inhibited by sumatriptan [61], as in spontaneous migraine [62]. One recent study has not detected CGRP level changes in migraine sufferers, suggesting that CGRP release does not provide a diagnostic tool [63], although the likelihood of a false negative result must be considered, given the strategy of sampling in patients’ homes. It is of interest in this regard that compounds that have not shown activity in migraine [64,65], notably the conformationally restricted analogue of sumatriptan, CP122 288 [66], and the conformationally restricted analogue of zolmitriptan, 4991w93 [67], were ineffective inhibitors of CGRP release with superior sagittal sinus stimulation in the cat. The recent development of a non-peptide highly specific CGRP receptor antagonist and the announcement of proof-of-concept for a CGRP receptor antagonist in
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acute migraine [68] firmly establish this as a novel and important new emerging principle for acute migraine. Also, the lack of any effect of CGRP blockers on the PPE model [35] explains in part why that model has proved inadequate to be translated into human therapeutic approaches. The trigeminocervical complex Stimulation of the superior sagittal sinus activates neurons in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in the cat [69] and monkey [70], the trigeminocervical complex. This group of cells provides an anatomical and physiological explanation for the pain at the back of the head in migraine. Experimental pharmacological evidence suggests that some abortive anti-migraine drugs, such as ergot derivatives [47], acetylsalicylic acid [71], sumatriptan [72], eletriptan [73], naratriptan [74], rizatriptan [75] and zolmitriptan [76], can act at these second-order neurons to reduce cell activity, suggesting an additional possible site for therapeutic intervention in migraine. This action involves each of the 5-hydroxytryptamine (serotonin) (5-HT)1B, 5-HT1D and 5HT1F receptor subtypes [77], and is consistent with the localization of these receptors on peptidergic nociceptors [78]. Interestingly, triptans also influence the CGRP promoter [79], regulate CGRP secretion from neurons in culture, and their receptors can only be available after activation by an afferent stimulus [80]. This observation might explain the triptan paradox that early use of injectable sumatriptan is not effective compared with placebo [81]. Consistent with a central effect, local microtionophoresis of CGRP antagonists into the trigeminocervical complex can inhibit nociceptive trigeminovascular transmission [82]. Furthermore, the demonstration that part of the action of triptans is postsynaptic with either 5-HT1B or 5-HT1D receptors located non-presynatically [83] offers a prospect of highly anatomically localized treatment options. Higher order processing Following transmission in the caudal brain stem and high cervical spinal cord, information is relayed rostrally (Table 2). Processing of vascular nociceptive signals in the thalamus occurs in the ventroposteromedial (VPM) thalamus, medial nucleus of the posterior complex and in the
Table 2. Neuroanatomical processing of vascular head pain Structure Target innervation Cranial vessels Dura mater 1 st 2 nd 3 rd
Modulatory Final
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Comments
Ophthalmic branch of trigeminal nerve Trigeminal ganglion Trigeminal nucleus (quintothalamic tract) Thalamus
Midbrainm Hypothalamus Cortex
Middle cranial fossa Trigeminal nucleus caudalis, and C1 and C2 dorsal horns Ventrobasal complex Medial nucleus of posterior group Intralaminar complex Periaqueductal grey matter ? Insulae Frontal cortex Anterior cingulate cortex Basal ganglia
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intralaminar thalamus [84]. Zagami and Goadsby [84] have shown, by application of capsaicin to the superior sagittal sinus, that trigeminal projections with a high degree of nociceptive input are processed in neurons particularly in the VPM thalamus and in its ventral periphery. These VPM neurons can be modulated by activation of g-aminobutyric acid (GABA)A inhibitory receptors and, perhaps of more-direct clinical relevance, by propranolol but with a b1-adrenoceptor mechanism [85]. Remarkably, triptans through 5-HT1B or 5-HT1D mechanisms can also inhibit VPM neurons locally, as demonstrated by microiontophoretic application [86], suggesting a hitherto unconsidered locus of action for triptans in acute migraine. Central modulation of trigeminal pain Brain imaging in humans Functional brain imaging with positron emission tomography (PET) has shown activation of the dorsal midbrain, including the periaqueductal grey (PAG), and the dorsal pons close to the locus coeruleus, in studies during migraine without aura [87]. Dorsolateral pontine activation is observed with PET in spontaneous episodic [88] and chronic migraine [89] and with nitrogylcerintriggered attacks [90,91]. What might dysfunction of these brain areas lead to? Animal experimental studies of sensory modulation It has been shown in experimental animal models that stimulation of nucleus locus coeruleus, which is the main central noradrenergic nucleus, reduces cerebral blood flow in a frequency-dependent manner [92] through an a2adrenoceptor-linked mechanism. This reduction is maximal in the occipital cortex [93] and would be consistent with recent imaging data showing a static flow reduction in occipital cortex in migraine without aura [94]. Although a 25% reduction in cerebral blood flow is observed, extracerebral vasodilatation occurs in parallel [92]. In addition, the main serotonin-containing nucleus in the brain stem – the midbrain dorsal raphe nucleus – can increase cerebral blood flow when activated [95]. Furthermore, stimulation of PAG inhibits sagittal-sinus-evoked trigeminal neuronal activity in cat, whereas blockade of P/Q-type voltage-gated Ca2+ channels in the PAG facilitates trigeminovascular nociceptive processing [46] with the local GABA system in the PAG still intact. What is migraine? Migraine is an inherited, episodic disorder involving sensory sensitivity. Patients complain of throbbing pain in the head, but there is no reliable relationship between vessel diameter and the pain [96] or its treatment [97]. Patients also complain of discomfort from normal lights and sounds. Some patients perceive pleasant odours as unpleasant. Normal movement of the head causes pain, and many patients report a sense of unsteadiness as if they have just stepped off a boat. The anatomical connections of, for example, the pain pathways are clear; the ophthalmic division of the trigeminal nerve subserves sensation within the cranium. The convergence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary www.sciencedirect.com
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headache. The genetics of ionopathies is opening up a plausible way to think about the episodic nature of migraine. However, where is the lesion and what is the pathology? If one considers what patients report, then perhaps they provide the answer to this question. Migraine aura cannot be the trigger; there is no evidence after 4000 years that aura occurs in >30% of migraine patients. Aura can be experienced without pain at all, and is also observed in the other primary headaches. The basis of the problem is likely to be abnormal central processing of normal sensory signals. If migraine was basically a sensory attentional problem with changes in cortical synchronisation [98] and hypersynchronisation [99], all its clinical manifestations and electrophysiological changes might be accounted for in a single over-arching pathophysiological hypothesis of a disturbance of subcortical sensory modulation systems. Unravelling the physiology and pharmacology of migraine and seeking its basic molecular mechanisms will provide treatments for many disabled patients and insights into some fascinating aspects of human neurobiology. References 1 Lipton, R.B. et al. (2001) Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41, 646–657 2 Andlin-Sobocki, P. et al. (2005) Cost of disorders of the brain in Europe. Eur. J. Neurol. 12 (Suppl 1), 1–27 3 Olesen, J. et al. (2005) The Headaches Lippincott, Williams & Wilkins 4 Lance, J.W. and Goadsby, P.J. (2005) Mechanism and Management of Headache (7th ed.), Elsevier 5 Goadsby, P.J. et al. (2002) Migraine – current understanding and treatment. N. Engl. J. Med. 346, 257–270 6 Bergerot, A. et al. (2006) Animal models of migraine: looking at the component parts of a complex disorder. Eur. J. Neurosci. 24, 1517–1534 7 Silberstein, S.D. et al. (2002) Headache in Clinical Practice (second ed.), Martin Dunitz 8 Goadsby, P.J. and Kullmann, D.K. (2005) Another migraine gene – further opportunities to understand an important disorder. Lancet 366, 345–346 9 Ophoff, R.A. et al. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 10 De Fusco, M. et al. (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump a2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 11 Dichgans, M. et al. (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A causes familial hemiplegic migraine. Lancet 366, 371–377 12 Pietrobon, D. and Striessnig, J. (2003) Neurobiology of migraine. Nat. Rev. Neurosci. 4, 386–398 13 van den Maagdenberg, A.M.J.M. et al. (2004) A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701–710 14 Goadsby, P.J. (2004) Migraine aura: a knock-in mouse with a knock-out message. Neuron 41, 679–680 15 Cao, Y.Q. and Tsien, R.W. (2005) Effects of familial hemiplegic migraine type I mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc. Natl. Acad. Sci. U. S. A. 102, 2590–2595 16 Lauritzen, M. (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 17 Moskowitz, M.A. et al. (2004) Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55, 276–280 18 Olsen, J. (2004) The International Classification of Headache Disorders (second edition). Cephalalgia 24 (Suppl 1), 1–160 19 Rasmussen, B.K. and Olesen, J. (1992) Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12, 221–228
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47 Hoskin, K.L. et al. (1996) Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiology study. Brain 119, 249–256 48 Storer, R.J. and Goadsby, P.J. (1997) Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 120, 2171–2177 49 Pozo-Rosich, P. and Oshinsky, M. (2005) Effect of dihydroergotamine (DHE) on central sensitisation of neurons in the trigeminal nucleus caudalis. Neurology 64 (Suppl 1), A151 50 Kaube, H. et al. (1993) Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. Headache 33, 541–550 51 Jakubowski, M. et al. (2005) Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors. Headache 45, 850–861 52 Goadsby, P.J. et al. (1988) Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann. Neurol. 23, 193–196 53 Goadsby, P.J. and Macdonald, G.J. (1985) Extracranial vasodilatation mediated by VIP (Vasoactive Intestinal Polypeptide). Brain Res. 329, 285–288 54 Goadsby, P.J. et al. (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 55 Gallai, V. et al. (1995) Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15, 384–390 56 Goadsby, P.J. and Edvinsson, L. (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 117, 427–434 57 Fanciullacci, M. et al. (1995) Increase in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 60, 119–123 58 Goadsby, P.J. and Edvinsson, L. (1996) Neuropeptide changes in a case of chronic paroxysmal hemicrania- evidence for trigeminoparasympathetic activation. Cephalalgia 16, 448–450 59 Afridi, S. et al. (2004) Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 110, 675–680 60 Juhasz, G. et al. (2003) NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 106, 461– 470 61 Juhasz, G. et al. (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25, 179–183 62 Goadsby, P.J. and Edvinsson, L. (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 63 Tvedskov, J.F. et al. (2005) No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann. Neurol. 58, 561–568 64 Roon, K.I. et al. (2000) No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized double-blind placebo-controlled clinical trials. Ann. Neurol. 47, 238–241 65 Earl, N.L. et al. (1999) 4991W93 Investigator Group. Efficacy and tolerability of the neurogenic inflammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia 19, 357 66 Knight, Y.E. et al. (1999) Blockade of CGRP release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. Neuropeptides 33, 41–46 67 Knight, Y.E. et al. (2001) 4991W93 inhibits release of calcitonin generelated peptide in the cat but only at doses with 5HT1B/1D receptor agonist activity. Neuropharmacology 40, 520–525 68 Olesen, J. et al. (2004) Calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks. N. Engl. J. Med. 350, 1104–1110 69 Kaube, H. et al. (1993) Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Brain Res. 629, 95–102 70 Goadsby, P.J. and Hoskin, K.L. (1997) The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J. Anat. 190, 367–375
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71 Kaube, H. et al. (1993) Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. Headache 33, 541–550 72 Kaube, H. et al. (1993) Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Br. J. Pharmacol. 109, 788–792 73 Goadsby, P.J. and Hoskin, K.L. (1999) Differential effects of low dose CP122,288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat. Pain 82, 15–22 74 Goadsby, P.J. and Knight, Y.E. (1997) Inhibition of trigeminal neurons after intravenous administration of naratriptan through an action at the serotonin (5HT1B/1D) receptors. Br. J. Pharmacol. 122, 918–922 75 Cumberbatch, M.J. et al. (1997) Rizatriptan has central antinociceptive effects against durally evoked responses. Eur. J. Pharmacol. 328, 37–40 76 Goadsby, P.J. and Hoskin, K.L. (1996) Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine? Pain 67, 355–359 77 Goadsby, P.J. and Classey, J.D. (2003) Evidence for 5-HT1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience 122, 491–498 78 Potrebic, S. et al. (2003) Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J. Neurosci. 23, 10988–10997 79 Durham, P.L. et al. (1997) Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J. Neurosci. 17, 9545– 9553 80 Ahn, A.H. and Basbaum, A.I. (2006) Tissue injury regulates serotonin 1D receptor expression: implications for the control of migraine and inflammatory pain. J. Neurosci. 26, 8332–8338 81 Bates, D. et al. (1994) Subcutaneous sumatriptan during the migraine aura. Neurology 44, 1587–1592 82 Storer, R.J. et al. (2004) Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br. J. Pharmacol. 142, 1171–1181 83 Goadsby, P.J. et al. (2001) Evidence for postjunctional serotonin (5HT1) receptors in the trigeminocervical complex. Ann. Neurol. 50, 804–807 84 Zagami, A.S. and Goadsby, P.J. (1991) Stimulation of the superior sagittal sinus increases metabolic activity in cat thalamus.. In New
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Advances in Headache Research (Rose, F.C., ed.), pp. 169–171, SmithGordon and Co Ltd Shields, K.G. and Goadsby, P.J. (2005) Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 128, 86–97 Shields, K.G. and Goadsby, P.J. (2006) Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol. Dis. 23, 491–501 Weiller, C. et al. (1995) Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1, 658–660 Afridi, S. et al. (2005) A PET study in spontaneous migraine. Arch. Neurol. 62, 1270–1275 Matharu, M.S. et al. (2004) Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 127, 220–230 Bahra, A. et al. (2001) Brainstem activation specific to migraine headache. Lancet 357, 1016–1017 Afridi, S. et al. (2005) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128, 932–939 Goadsby, P.J. et al. (1982) Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res. 249, 247–254 Goadsby, P.J. and Duckworth, J.W. (1989) Low frequency stimulation of the locus coeruleus reduces regional cerebral blood flow in the spinalized cat. Brain Res. 476, 71–77 Denuelle, M. et al. (2004) Brainstem and hypothalamic activation in spontaneous migraine attacks. Cephalalgia 24, 775–814 Goadsby, P.J. et al. (1991) Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 31, 365–371 Kruuse, C. et al. (2003) Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126, 241–247 Limmroth, V. et al. (1996) Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J. Neurol. Sci. 138, 60–65 Niebur, E. et al. (2002) Synchrony: a neural mechanism for attentional selection? Curr. Opin. Neurobiol. 12, 190–194 Angelini, L. et al. (2004) Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys. Rev. Lett. 93, 038103-1-038103-4
Articles of interest in other Current Opinion journals Glucose metabolism and cancer Reuben J. Shaw, Current Opinion in Cell Biology, vol. 18, pp. 598–608 Opportunities for structure-based design of protease-directed drugs Peer R.E. Mittl and Markus G. Gu¨tter, Current Opinion in Structural Biology, doi: 10.1016/j.sbi.2006.10.1014 Basal ganglia oscillations and pathophysiology of movement disroders Michal Rivlin-Etzion, Odeya Marmor, Gali Heimer, Aeyal Raz, Asaph Nini and Hagai Bergman, Current Opinion in Neurobiology, doi: 10.1016/j.conb.2006.10.002 NMDA receptor and schizophrenia Lars V Kristiansen, Ibone Huerta, Monica Beneyto and James H Meador-Woodruff, Current Opinion in Pharmacology, doi: 10.1016/j.coph.2006.08.013 www.sciencedirect.com
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Recent advances in understanding migraine mechanisms, molecules and therapeutics Peter J. Goadsby Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK WC1N 3BG
Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca2+ channel), ATP1A2 (N+–K+-ATPase) and SCN1A (Na+ channel) genes. Physiological studies in humans and studies of the experimental correlate – cortical spreading depression (CSD) – provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulation – a system failure of normal sensory processing. Introduction Migraine is an episodic brain disorder that affects 15% of the population [1]; it can be highly disabling, and has been estimated to be the most costly neurological disorder in the European Community at >s27 billion per year [2]. Migraine is a familial episodic disorder, the key marker of which is headache with certain associated features (Table 1). By studying its component parts, one can gain insights into potential molecular mechanisms that might direct the development of new therapies. For a more-general clinical account of the disorder and its treatments, texts are available [3–5]. Here, I consider the known pathophysiology of migraine and attempt to integrate the molecular mechanisms that are emerging. It must be said that the molecular basis of migraine is not understood yet, although one can infer much from what is known of the pathophysiology and its treatment. The elements to be considered are: (i) genetics of migraine; (ii) physiological basis of the aura; (iii) Corresponding author: Goadsby, P.J. ([email protected]). Available online 1 December 2006. www.sciencedirect.com
physiology and pharmacology of the pain-producing innervation of the dura mater and cranial vessels – the trigeminovascular system; and (iv) brainstem and diencephalic modulatory systems that influence trigeminal pain transmission and other sensory modality processing. Migraine is a form of sensory processing disturbance with wide ramifications within the CNS. Although pain pathways are used as an example, it is important to remember that migraine is a complex disorder for which a unitary molecular explanation seems a long way off. Animal models of the constituent parts of the disorder have been useful in dissecting some of the mechanisms, although each of them has its limitations [6]. Genetics of migraine One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder. It is clear from clinical practice that many patients have firstdegree relatives who also suffer from migraine [4,7]. Transmission of migraine from parents to children has been reported as early as the seventeenth century, and numerous published studies have described a positive family history [3]. Identification of the genes that are responsible for the inherited component has been fruitful in beginning to point to particular molecular mechanisms of the disorder. This work has taken advantage of the clear inherited aura phenotype of familial hemiplegic migraine (FHM) to suggest that migraine aura has a crucial ionopathic component [8]. Familial hemiplegic migraine (FHM) The biological basis for the linkage of FHM to chromosome 19p13 is the presence of mutations [9] in the Cav2.1 (P/Q) type voltage-gated Ca2+ channel gene (CACNA1A). Now known as FHM-I, this mutation is responsible for 50% of identified FHM families. One consequence of this mutation is enhanced glutamate release. Mutations in the ATP1A2 gene (also known as FHM-II) [10] are responsible for 20% of FHM families. The ATP1A2 gene encodes a Na+–K+ ATPase and the mutation results in a smaller electrochemical gradient for Na+. One effect of this is to reduce or inactivate astrocytic glutamate transporters, leading to a build-up of synaptic glutamate. Interestingly, the phenotype of some FHM-II patients involves epilepsy. Recently, FHM-III has been identified as a mutation in a Na+ channel gene (SCN1A) [11]. FHM-III would facilitate repetitive
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Table 1. International Headache Society features of migraine [18] Repeated episodic headache (4–72 hrs) with the following features: Any one of: Any two of: Nausea and/or vomiting Unilateral Photophobia and phonophobia Throbbing Worsened by movement Moderate or severe
high-frequency discharges that might also increase synaptic glutamate levels. The consequence of all these mutations has been considered and debated [12]. Linking channel disturbances for the first time to the aura process has shown that human mutations that are expressed in a knock-in mouse produce a reduced threshold for cortical spreading depression (CSD) [13], which has profound implications for understanding migraine aura [14]. These mutations seem to produce a net gain-of-function effect because the cortex becomes more susceptible to stimuli that trigger CSD, although this is not universally accepted [15]. CSD is widely considered to be at the basis for migraine aura [16], and the convergence of each FHM mutation to increase synaptic glutamate is an attractive way to conceptualise how CSD might be more-easily triggered in FHM patients [17]. Migraine aura Migraine aura is defined as a focal neurological disturbance that manifests itself as visual, sensory or motor symptoms [18]. It is observed in 30% of migraine patients [19], and it is clearly neurally driven [16]. The hypothesis that the aura is the human equivalent of CSD of Leao [20] has been well established [16]. Observations of human patients have suggested that human aura has its equivalent in animals CSD [21]. An area of controversy surrounds whether aura triggers the rest of the attack and is painful [17]. Based on the available experimental and clinical data, Goadsby [22] is not at all convinced that aura is painful, but this does not diminish its interest or the importance of understanding it. Indeed, therapeutic developments might shed more light on the relationship between aura and headache, and on the molecular basis for aura. Tonabersat (SB-220453) is an inhibitor of CSD that has entered clinical trials of migraine. Tonabersat inhibits CSD, CSD-induced nitric-oxide (NO) release and cerebral vasodilation [23]. Tonabersat does not constrict isolated human blood vessels [24], but inhibits trigeminally induced craniovascular effects [25]. Remarkably, topiramate, a proven preventive agent in migraine [26], also inhibits CSD in cats and rats [27]. Topiramate inhibits trigeminal neurons that are activated by nociceptive intracranial afferents [28], but not by a local trigeminal mechanism [29]. Ayata et al. [30] have attempted to correlate the preventive action of a range of medicines with an effect on CSD. These authors studied topiramate, valproate, amitriptyline, propranolol and methysergide. Topiramate, valproate and amitriptyline inhibited CSD induction at doses that are typically used in rodent studies, none of which was similar to the dose that is used in migraine www.sciencedirect.com
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prevention. The dose of propranolol used was four times that reported in previous rat studies [31], whereas methysergide had no effect on speed of propagation [30]. CSD inhibition might be a model system for the study of migraine to help developing preventive medicines, although this seems far from clearly established. Headache pathophysiology Peripheral mechanisms Throbbing pain is a classical and frequent, although not invariable, clinical manifestation of migraine. It has been therefore suggested that cranial vessels, their innervation or the control mechanisms that gate input from these structures have a role in this disorder. The dura mater is innervated by branches of the first (ophthalmic) division of the trigeminal nerve. Stimulation of the trigeminal ganglion results in plasma protein extravasation (PPE) in the dura mater [32], cerebral vasodilation [33] and local nerve stimulation in dural vasodilation [34]. PPE has two important components: vasodilation and leakage of plasma proteins. The extravasation component relies on the substance P (neurokinin-1) receptor [35], which is highly effective in blocking dural PPE [36]. CSD can activate trigeminal neurons in the rat [37] and matrix metalloproteinase (MMP)-9, which leads to increased vascular permeability [38]. Repeated attacks on membrane integrity by MMPs seem an implausible scenario in a disorder, the natural course of which is to remit [1]. Moreover, it is clear from clinical studies [39] that neurokinin-1 antagonists are not effective in migraine and, indeed, there is no direct convincing evidence for the role of dural PPE in human migraine [40]. Sensitisation and migraine Although it is highly improbable that there is a significant sterile inflammatory response in the dura mater during migraine, it is clear that a form of sensitisation takes place during migraine, because allodynia – pain from non-noxious stimuli – is common. About two-thirds of migraine patients complain of allodynia [41]. It has been suggested in an open-label study that triptan effects might be predicted by the presence or absence of allodynia, where its presence indicates a poor clinical response [42]. However, results from a placebo-controlled double-blind study suggest that allodynia, at least as reflected by sensitivity to cutaneous inputs, is not predictive of headache relief by a triptan in acute migraine [43]. Particularly interesting is the demonstration of allodynia in the upper limbs that are ipsilateral and contralateral to the pain. This finding is consistent with at least third-order neuronal sensitisation, such as sensitisation of thalamic neurons, placing the pathophysiology of this manifestation within the CNS. Sensitisation in migraine might be peripheral with local release of inflammatory markers that would activate trigeminal nociceptors [44]. More probable in migraine is a form of central sensitisation, which might be classic central sensitisation [45], or a form of disinhibitory sensitisation with dysfunction of descending modulatory pathways [46]. Just as dihydroergotamine (DHE) can block trigeminovascular nociceptive transmission [47], probably by a local effect in the trigeminocervical complex [48], DHE can
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block central sensitisation that is associated with dural stimulation by an ‘inflammatory soup’ [49]. Interestingly, aspirin is also effective in blocking second-order trigeminovascular neurons [50], and cyclooxygenase mechanisms might be important in allodynia [51]. Such observations are already being translated in clinical development through trials of combined triptan–non steroidal antiinflammatory drug (NSAID) combination medicines that might offer a therapeutic advantage in terms of headache recurrence. Neuropeptide release and migraine Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both calcitonin gene-related peptide (CGRP) and substance P (SP) [52]. In the cat, trigeminal ganglion stimulation also increases cerebral blood flow by a pathway traversing the greater superficial petrosal branch of the facial nerve [33], releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP) [53]. Stimulation of the more-specifically vascular painproducing superior sagittal sinus increases cerebral blood flow and jugular vein CGRP levels. Evidence from humans that CGRP level is elevated in the headache phase of migraine [54,55], cluster headache [56,57] and chronic paroxysmal hemicrania [58] supports the view that the trigeminovascular system might be activated for a protective role in these conditions. Moreover, NO-donor-triggered migraine, which is the typical form of migraine [59], also results in increased levels of CGRP [60] that are inhibited by sumatriptan [61], as in spontaneous migraine [62]. One recent study has not detected CGRP level changes in migraine sufferers, suggesting that CGRP release does not provide a diagnostic tool [63], although the likelihood of a false negative result must be considered, given the strategy of sampling in patients’ homes. It is of interest in this regard that compounds that have not shown activity in migraine [64,65], notably the conformationally restricted analogue of sumatriptan, CP122 288 [66], and the conformationally restricted analogue of zolmitriptan, 4991w93 [67], were ineffective inhibitors of CGRP release with superior sagittal sinus stimulation in the cat. The recent development of a non-peptide highly specific CGRP receptor antagonist and the announcement of proof-of-concept for a CGRP receptor antagonist in
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acute migraine [68] firmly establish this as a novel and important new emerging principle for acute migraine. Also, the lack of any effect of CGRP blockers on the PPE model [35] explains in part why that model has proved inadequate to be translated into human therapeutic approaches. The trigeminocervical complex Stimulation of the superior sagittal sinus activates neurons in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in the cat [69] and monkey [70], the trigeminocervical complex. This group of cells provides an anatomical and physiological explanation for the pain at the back of the head in migraine. Experimental pharmacological evidence suggests that some abortive anti-migraine drugs, such as ergot derivatives [47], acetylsalicylic acid [71], sumatriptan [72], eletriptan [73], naratriptan [74], rizatriptan [75] and zolmitriptan [76], can act at these second-order neurons to reduce cell activity, suggesting an additional possible site for therapeutic intervention in migraine. This action involves each of the 5-hydroxytryptamine (serotonin) (5-HT)1B, 5-HT1D and 5HT1F receptor subtypes [77], and is consistent with the localization of these receptors on peptidergic nociceptors [78]. Interestingly, triptans also influence the CGRP promoter [79], regulate CGRP secretion from neurons in culture, and their receptors can only be available after activation by an afferent stimulus [80]. This observation might explain the triptan paradox that early use of injectable sumatriptan is not effective compared with placebo [81]. Consistent with a central effect, local microtionophoresis of CGRP antagonists into the trigeminocervical complex can inhibit nociceptive trigeminovascular transmission [82]. Furthermore, the demonstration that part of the action of triptans is postsynaptic with either 5-HT1B or 5-HT1D receptors located non-presynatically [83] offers a prospect of highly anatomically localized treatment options. Higher order processing Following transmission in the caudal brain stem and high cervical spinal cord, information is relayed rostrally (Table 2). Processing of vascular nociceptive signals in the thalamus occurs in the ventroposteromedial (VPM) thalamus, medial nucleus of the posterior complex and in the
Table 2. Neuroanatomical processing of vascular head pain Structure Target innervation Cranial vessels Dura mater 1 st 2 nd 3 rd
Modulatory Final
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Comments
Ophthalmic branch of trigeminal nerve Trigeminal ganglion Trigeminal nucleus (quintothalamic tract) Thalamus
Midbrainm Hypothalamus Cortex
Middle cranial fossa Trigeminal nucleus caudalis, and C1 and C2 dorsal horns Ventrobasal complex Medial nucleus of posterior group Intralaminar complex Periaqueductal grey matter ? Insulae Frontal cortex Anterior cingulate cortex Basal ganglia
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intralaminar thalamus [84]. Zagami and Goadsby [84] have shown, by application of capsaicin to the superior sagittal sinus, that trigeminal projections with a high degree of nociceptive input are processed in neurons particularly in the VPM thalamus and in its ventral periphery. These VPM neurons can be modulated by activation of g-aminobutyric acid (GABA)A inhibitory receptors and, perhaps of more-direct clinical relevance, by propranolol but with a b1-adrenoceptor mechanism [85]. Remarkably, triptans through 5-HT1B or 5-HT1D mechanisms can also inhibit VPM neurons locally, as demonstrated by microiontophoretic application [86], suggesting a hitherto unconsidered locus of action for triptans in acute migraine. Central modulation of trigeminal pain Brain imaging in humans Functional brain imaging with positron emission tomography (PET) has shown activation of the dorsal midbrain, including the periaqueductal grey (PAG), and the dorsal pons close to the locus coeruleus, in studies during migraine without aura [87]. Dorsolateral pontine activation is observed with PET in spontaneous episodic [88] and chronic migraine [89] and with nitrogylcerintriggered attacks [90,91]. What might dysfunction of these brain areas lead to? Animal experimental studies of sensory modulation It has been shown in experimental animal models that stimulation of nucleus locus coeruleus, which is the main central noradrenergic nucleus, reduces cerebral blood flow in a frequency-dependent manner [92] through an a2adrenoceptor-linked mechanism. This reduction is maximal in the occipital cortex [93] and would be consistent with recent imaging data showing a static flow reduction in occipital cortex in migraine without aura [94]. Although a 25% reduction in cerebral blood flow is observed, extracerebral vasodilatation occurs in parallel [92]. In addition, the main serotonin-containing nucleus in the brain stem – the midbrain dorsal raphe nucleus – can increase cerebral blood flow when activated [95]. Furthermore, stimulation of PAG inhibits sagittal-sinus-evoked trigeminal neuronal activity in cat, whereas blockade of P/Q-type voltage-gated Ca2+ channels in the PAG facilitates trigeminovascular nociceptive processing [46] with the local GABA system in the PAG still intact. What is migraine? Migraine is an inherited, episodic disorder involving sensory sensitivity. Patients complain of throbbing pain in the head, but there is no reliable relationship between vessel diameter and the pain [96] or its treatment [97]. Patients also complain of discomfort from normal lights and sounds. Some patients perceive pleasant odours as unpleasant. Normal movement of the head causes pain, and many patients report a sense of unsteadiness as if they have just stepped off a boat. The anatomical connections of, for example, the pain pathways are clear; the ophthalmic division of the trigeminal nerve subserves sensation within the cranium. The convergence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary www.sciencedirect.com
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headache. The genetics of ionopathies is opening up a plausible way to think about the episodic nature of migraine. However, where is the lesion and what is the pathology? If one considers what patients report, then perhaps they provide the answer to this question. Migraine aura cannot be the trigger; there is no evidence after 4000 years that aura occurs in >30% of migraine patients. Aura can be experienced without pain at all, and is also observed in the other primary headaches. The basis of the problem is likely to be abnormal central processing of normal sensory signals. If migraine was basically a sensory attentional problem with changes in cortical synchronisation [98] and hypersynchronisation [99], all its clinical manifestations and electrophysiological changes might be accounted for in a single over-arching pathophysiological hypothesis of a disturbance of subcortical sensory modulation systems. Unravelling the physiology and pharmacology of migraine and seeking its basic molecular mechanisms will provide treatments for many disabled patients and insights into some fascinating aspects of human neurobiology. References 1 Lipton, R.B. et al. (2001) Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41, 646–657 2 Andlin-Sobocki, P. et al. (2005) Cost of disorders of the brain in Europe. Eur. J. Neurol. 12 (Suppl 1), 1–27 3 Olesen, J. et al. (2005) The Headaches Lippincott, Williams & Wilkins 4 Lance, J.W. and Goadsby, P.J. (2005) Mechanism and Management of Headache (7th ed.), Elsevier 5 Goadsby, P.J. et al. (2002) Migraine – current understanding and treatment. N. Engl. J. Med. 346, 257–270 6 Bergerot, A. et al. (2006) Animal models of migraine: looking at the component parts of a complex disorder. Eur. J. Neurosci. 24, 1517–1534 7 Silberstein, S.D. et al. (2002) Headache in Clinical Practice (second ed.), Martin Dunitz 8 Goadsby, P.J. and Kullmann, D.K. (2005) Another migraine gene – further opportunities to understand an important disorder. Lancet 366, 345–346 9 Ophoff, R.A. et al. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 10 De Fusco, M. et al. (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump a2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 11 Dichgans, M. et al. (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A causes familial hemiplegic migraine. Lancet 366, 371–377 12 Pietrobon, D. and Striessnig, J. (2003) Neurobiology of migraine. Nat. Rev. Neurosci. 4, 386–398 13 van den Maagdenberg, A.M.J.M. et al. (2004) A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701–710 14 Goadsby, P.J. (2004) Migraine aura: a knock-in mouse with a knock-out message. Neuron 41, 679–680 15 Cao, Y.Q. and Tsien, R.W. (2005) Effects of familial hemiplegic migraine type I mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc. Natl. Acad. Sci. U. S. A. 102, 2590–2595 16 Lauritzen, M. (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 17 Moskowitz, M.A. et al. (2004) Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55, 276–280 18 Olsen, J. (2004) The International Classification of Headache Disorders (second edition). Cephalalgia 24 (Suppl 1), 1–160 19 Rasmussen, B.K. and Olesen, J. (1992) Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12, 221–228
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