Vascular Pharmacology 43 (2005) 176 – 187 www.elsevier.com/locate/vph

Migraine: Current concepts and emerging therapies

D.K. Arulmozhi a,b,*, A. Veeranjaneyulu a, S.L. Bodhankar b

aNew Chemical Entity Research, Lupin Research Park, Village Nande, Taluk Mulshi, Pune 411 042, Maharashtra, India bDepartment of Pharmacology, Bharati Vidyapeeth, Poona College of Pharmacy, Pune 411 038, Maharashtra, India

Received 23 April 2005; received in revised form 17 June 2005; accepted 11 July 2005

Abstract

Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating associated with photophobia, phonophobia, nausea and vomiting. Migraine affects a substantial fraction of world population and is a major cause of disability in the work place. Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing which causes the spreading depression and migraine) and neurogenic dural (release of inflammatory neuropeptides). The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder. The drugs used in the treatment of migraine either abolish the acute migraine or aim its prevention. The last decade has witnessed the advent of Sumatriptan and the Ftriptan_ class of 5-HT1B/1D receptor agonists which have well established efficacy in treating migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta adrenoceptor blockers and g-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non specific and not always effective. Despite such progress, in view of the complexity of the etiology of migraine, it still remains undiagnosed and available therapies are underused. In this article, the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed. Furthermore, the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine, with a special emphasis to calcitonin gene-related peptide, are critically evaluated. D 2005 Published by Elsevier Inc.

Keywords: Migraine; CGRP; ; Triptan

1. Introduction towards attacks and the cranial circulatory phenomenon appears to be secondary to a primary central Migraine is a chronic, often debilitating that disorder. affects 12% of the general population. This episodic brain The Headache Classification Committee of the Interna- disorder is characterized by unilateral throbbing headache tional Headache Society (IHS) published the classification lasting from 4 h to 3 days. Associated symptoms include and diagnostic criteria for headache disorders (International nausea vomiting and sensitivity to light, sound and head Headache Society, 2004). The terms Fcommon migraine_ movements (Silberstein, 2004). A working definition of and Fclassical migraine_ have been replaced by Fmigraine migraine is benign recurring headache and/or neurological without aura_ and Fmigraine with aura_ respectively. These dysfunction usually attended by pain-free interludes and operational criteria have been validated by different often provoked by stereotyped stimuli. Migraine is more approaches and have enabled to distinguish different head- common in females, with a hereditary predisposition ache entities in a reliable manner. Migraine apparently a global disorder, occurring in all races, cultures and geographical locations. Current figures * Corresponding author. Department of Pharmacology, New Chemical Entity Research, Lupin Research Park, Village Nande, Taluk Mulshi, Pune suggest that 18% of women and six percent of men suffer 411 042, Maharashtra, India. Tel.: +91 20 2512 6161; fax: +91 20 2512 6298. from migraine and those numbers are increasing. The Center E-mail address: [email protected] (D.K. Arulmozhi). for Disease Control reported a 60% increase in the disease

1537-1891/$ - see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.vph.2005.07.001 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 177 from 1980 to 1989. The highest incidence of migraine Table 1 occurs between the ages of 20 and 35 and often associated Diagnostic criteria of migraine with a positive family history of the disease (Liption and Migraine without aura Bigal, 2005). A. At least 5 attacks fulfilling B–D B. Headache attacks, lasting 4–72 h (untreated or unsuccessfully treated) Migraine has an enormous impact on society. Recent C. Headache has at least two of the following characteristics studies have evaluated the indirect and direct costs of 1. Unilateral localization migraine. Indirect costs include the aggregate effects of 2. Pulsating quality migraine on productivity at work (paid employment), in 3. Moderate to severe intensity performance of household work and in other roles. It was 4. Aggravation by walking stairs or similar routine physical activity D. During headache at least one of the following estimated that productivity losses due to migraine cost 1. Nausea and/or vomiting American employers $13 billion per year (Lipton et al., 2. Photophobia and phonophobia 2003). E. At least one of the following In the present review, the modern theories of migraine 1. History, physical- and neurological examinations do not suggest with respect to its diverse etiology as well the present association with head trauma, vascular or non-vascular disorders, use of or withdrawal from noxious substances, non-cephalic therapeutic targets and futuristic approaches for the acute infections, metabolic disorders or disorder or cranial or facial and prophylactic treatment of migraine are critically structures evaluated. 2. History and/or physical- and/or neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations 3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation with the disorder 2. Pathophysiology of migraine Migraine with aura 2.1. Clinical manifestations A. At least 2 attacks fulfilling B B. Migraine aura fulfills criteria for typical aura, hemiplegic aura, or Migraine is characterized by episodes of head pain that is basilar-type aura C. Not attributed to another disorder often throbbing and frequently unilateral and may be severe. In migraine without aura (previously known as common Typical aura migraine) attacks are usually associated with nausea, 1. Fully reversible visual, sensory, or speech symptoms (or any vomiting, or sensitivity to light, sound, or movement and combination) but no motor weakness when treated, the attacks typically last 4 to 72 h (Olesen and 2. Homonymous or bilateral visual symptoms including positive features (eg. Flicking of lights, spots, lines) or negative features (e.g. Loss of Lipton, 1994; Michel et al., 1993). A combination of vision), or unilateral sensory symptoms including positive features (e.g. features is required for the diagnosis, but not all features are Visual loss, pins and needles) or negative features (e.g. Numbness), or present in every attack or in every patient (Tables 1 and 2). any combination These symptoms do distinguish migraine from tension type 3. At least one of headache, the most common form of primary headache, a. At least one symptom develops gradually over a minimum of 5 min or different symptoms occur in succession or both which is characterized by the lack of associated features b. Each symptom lasts for at least 5 min and for no longer than 60 min (Silberstein, 2004). Any severe and recurrent headache is 4. Headache that meets criteria for migraine without aura begins during most likely a form of migraine and should be responsive to the aura or follows aura within 60 min antimigraine therapy (Lance, 2000). In 15% of patients migraine attacks are usually preceded or accompanied by transient focal neurotic symptoms, which are usually visual; 2.2. Genetics of migraine such patients have migraine with aura (previously known as classic migraine) (Rasmussen et al., 1992; Rasmussen and Migraine is best understood as primary disorder of pain Olesen, 1992). In a recent, large population-based study, (Silberstein, 2004). It is a form of neurovascular headache: 64% of patients with migraine had only migraine without a disorder in which neural events result in the dilation of aura, 18% had only migraine with aura and 13% had both blood vessels, which in turn, results in pain and further types of migraine (the remaining 5% had aura without nerve activation (Goadsby, 2001). Migraine is not caused headache). Thus, up to 31% of patients with migraine have by primary vascular event. Migraine attacks are episodic aura on some occasions (Launer et al., 1999), but clinicians and vary within and among the individuals. The variability who rely on the presence of aura for the diagnosis of is best explained by considering the biologic problem in migraine will miss many cases. migraine to be the dysfunction of an ion channel in the A recent survey by the World Health Organization aminergic brain stem nuclei that normally modulates (WHO), rates severe migraine, along with quadriplegia, sensory input and exerts neural influences on cranial psychosis, and , as one of the most disabling vessels (Silberstein, 2004). There is thus ample evidence chronic disorders (Menken et al., 2000). This ranking for genetic liability of migraine. Missense mutations in suggests that in the judgment of WHO, a day with severe CACNA1A gene, coding for the alpha subunit of a migraine is a disabling as a day with quadriplegia. neuronal P/Q type Ca2+ channel were discovered in patients 178 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 with familial (Montagna, 2004; Oph- Table 3 off et al., 1996). It is possible that other ion-channel Drugs for acute migraine attacks mutations contribute to migraine without aura, since it is Acute antimigraine Contraindications Indication primarily consist patients of migraine with aura who have agents been linked to the familial hemiplegic migraine locus Acetaminophen Liver disease Pregnancy (Terwindt et al., 2001). Aspirin Kidney disease, ulcer Coronary artery disease, peptic ulcer disease, transient The second gene responsible for familial hemeplegic disease ischeamic attack migraine was discovered to consist of the alpha 2 subunit of Nonsteroidal Kidney disease, peptic ulcer Arthritis the Na/K pump gene linked to chromosome 1q23. The anti-inflammatory disease, gastritis sodium-potassium pump catalyses the energy dependent drugs transport of Na+ and K+ across the cell membrane and is a Butalbital, Caffeine, Use of other sedative, history and analgesics of medication overuse heterodimer, composed of a catalytic and a glycoprotein Caffeine adjuvant Sensitivity to caffeine subunit. Two mechanisms were hypothesized to account for Isomethheptene Uncontrolled hypertension, an altered excitability of the memebrane in mutated cells; an coronary artery disease, increase in extra cellular K+ because of impaired clearance peripheral vascular disease of K+ might induce cortical depolarization and facilitate a Opioids Drug or substance misuse Pregnancy, rescue medication spreading depression (Montagna, 2004). Neuroleptics Parkinsons disease, Nausea, vomiting, prolonged QTc pregnancy Dihydroergotamine Prominent nausea Coronary artery disease, 3. Theories of migraine inj and intranasal or vomiting Ergotamine peripheral vascular disease, }uncontrolled hypertension Triptans 3.1. Vascular theory

In the late 1930’s, Harold Wolff became the first researcher to place migraine on a scientific basis, Wolf carotid vasculature (De Vries et al., 1996). Further studies measured the diameter of the extracranial (temporal) demonstrated that mainly 5-HT1B receptors mediate suma- arteries in patients suffering migraine attacks and found triptan-induced cranial vasoconstriction, involving carotid them to be dilated. These patients were treated with arteriovenous anastomoses and temporal and middle menin- vasoconstrictors (ergotamine) which relieved the pain geal arteries (De Vries et al., 1998). (Tables 2 and 3) and decreased the arterial dilation (Graham and Wolf, 1938). 3.2. Neurological theory Although subsequent events leading to headache (and associated symptoms) are not completely understood, the A second theory of migraine is the neurological theory of increased vascular pulsation may activate stretch receptors. migraine. This theory suggests that migraine arises as a This would, in turn increase the activity of neuropeptide result of abnormal neuronal firing and neurotransmitter containing (mainly calcitonin gene-related peptide (CGRP) release in brain neurons. This theory focuses on an perivascular nerves which may ultimately cause pain and explanation for certain symptoms, such as premonitory other associated symptoms (De Vries et al., 1999; Willems symptoms occurring prior to an attack (prodrome), which et al., 2003). are difficult to explain based on the vascular hypothesis. The In line with the finding that carotid arteriovenous fact that migraine begin and develop slowly anastomoses dilatation play a role in the pathogenesis of coupled to the fact that external factors, such as stress, and migraine, it is reasonable to believe that compounds which hunger can precipitate migraine attacks to pathologies produce a cranioselective vasoconstriction may have a arising in the neuronal system, thus supporting a neuro- potential therapeutic use in the treatment of migraine. In logical basis of migraine (Pearce, 1984). Cortical spreading anaesthetized dogs and pigs acutely acting antimigraine depression, an expanding depolarization of cortical neurons drugs, ergot alkaloids (ergotamine and dihydroergotamine) which is well characterized in many species but not in man and triptans (sumatriptan and second generation triptans) is often suggested to underlie the aura or prodrome produced potent vasoconstriction in the canine and porcine associated with initiation of migraine attack. During spread- ing depression, cortical function is disrupted subsequent to neuronal depolarization and increased extracellular potas- Table 2 Migraine treatment strategies sium. These cortical changes are thought to be the cause of Suppressing initiation and perpetuation of cortical spreading depression the transient sensory or motor impairments that frequently Inhibiting mechanism of neurovascular coupling neurogenic inflammation precede the painful period of a migraine attack. Inhibiting nociceptor activation Many investigators hypothesize that neuronal activation in Enhancing descending modulation migraine may be mediated by cortical spreading depression Blocking peripheral and central sensitization (CSD). In brief, CSD is a phenomenon of neuronal activation D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 179 followed by suppression, which progresses over the cortical neurogenic dural inflammation theory of migraine, release surface and spreads down into the depth of the sulci at a rate of these inflammatory neuropeptides in the dura mater of 2–8 mm/min. Coupled with this electrical phenomenon during migraine can act on vascular tissues to cause are cerebral blood flow changes that manifest as initial vasodilatation, plasma protein extravasation in the surround- hyperemia followed by spreading oligemia. Experimentally, ing area, endothelial changes, platelet aggregation and CSD can be triggered by trauma and by chemicals such as subsequent release of serotonin and other mediators, white hydrogen ions, potassium, and glutamate. The coupling cell adhesion and subsequent inflammation (Dimitriadou et between CSD and activation of the vascular nociceptives is al., 1991, 1992). CGRP plays a facilitatory role in this not fully elucidated. Potential culprits include release of nitric process (Brain and Williams, 1985). Whereas oxide (NO) and atrionatriuretic factor (ANP), spread of induces extravasation via activation of NK1 receptors, astrocytic calcium waves to pial arachnoid cells with release of CGRP enhances the effects of substance P by subsequent activation of intradural nociceptives, descending increasing dural blood flow and by inhibiting an extrac- activation of noradrenergic pathways, changes in blood flow, ellular enzyme that normally can metabolize substance P. and vascular dilatation with nociceptive sensitization (Lash- Therefore, these two sensory neuropeptides act in concert to ley, 1941; Lashley et al., 1981; Olesen et al., 1981). produce painful dural inflammation. Although not reliably Several inconsistencies exist with the neurological theory demonstrated, increased cranial venous concentration of of migraine. In part, these are related to the fact that the CGRP have been observed during a migraine attack and the brain itself does not contain pain sensory fibers although elevated concentrations of CGRP have returned to normal pain fibers are located in the meninges. Furthermore, following treatment of the migraine in the serotonergic although stress may precipitate migraine, the actual occur- agonists (Arulmani et al., 2004). rence of the headache pain generally prevails after, rather This theory is in consistent with the proposal that sero- than during the stressful circumstance. tonergic agonist alleviate the acute pain of migraine by inhibiting the release of substance P and CGRP from trige- 3.3. Neurogenic theory minal sensory afferent neurons surrounding the meninges.

Lance et al. (1983) demonstrated that blood flow changes similar to those known to occur in migraine could be 4. Pain mechanisms in migraine produced by electrically stimulating brain stem structures. This finding led to the neurogenic theory. Stimulation studies The pathogenesis of pain in migraine is not completely investigated the relationship between the trigeminal nerve understood so far, but three key factors merit consider- and the cranial vasculature. Moskowitz (1992) showed that ations are: the cranial blood vessels, the trigeminal trigeminovascular axons from blood vessels of the pia mater innervation of the vessels, and the reflex connection of and dura mater release vasoactive peptides producing a sterile the trigeminal system in the cranial parasympathetic inflammatory reaction with pain. During this neurogenic outflow. The substance of the brain is largely insensate; inflammation, the trigeminal ganglion is stimulated and this pain can be generated by large cranial vessels, proximal induces neurogenic protein extravasation. Vasodilatory pep- intracranial vessels or by the dura mater (Martin et al., tides then released, including calcitonin gene related peptide 1993; Feindel et al., 1960). These vessels are innervated (CGRP), substance P (SP) and . by branches of the ophthalmic division of the trigeminal Neurogenic theory is an attempt to reconcile the vascular nerve, whereas the structures of the posterior fossa are changes in the neuronal dysfunction that may occur in innervated by branches of the C2 nerve roots. In non- migraine headache and proposes that migraine pain is human primates, stimulation of vascular afferents leads to associated with inflammation and dilation of the meninges, the activation of neurons in the superficial layers of the particularly the dura, a membrane surrounding the brain. trigeminal nucleus caudalis in the region of the craniome- Neurogenic dural inflammation is thought to result from the dullary junction and the superficial layers of the dorsal actions of inflammatory neuropeptides released from the horns C1 and C2 levels of the trigeminocer- primary sensory nerve terminals innervating the dural blood vical complex (Hoskin et al., 1999; Goadsby and Hoskin, vessels. In fact, the dural membrane surrounding the brain is 1997). Similarly, stimulation of branches of C2 activates the source for the majority of intracranial pain afferents and neurons in the same regions of the brain (Kerr, 1960). The dural stimulation produces headache like pain in human involvement of ophthalmic division of the trigeminal nerve (Moskowitz, 1992, 1993). Stimulation or inflammation of and the overlap with structures innervated by C2 explain sensory fibers release the inflammatory neuropeptides, the common distribution of migraine pain over the frontal substance P and calcitonin gene-related peptide onto dural and temporal regions, as well as involvement of parietal, tissue, where these peptides produce a local response called occipital and high cervical regions by what is, in essence, neurogenic inflammation. Neurogenic inflammation may referred pain. lower the nociceptive threshold required to stimulate Peripheral trigeminal activation in migraine is evidenced meningial sensory fibers (Moskowitz, 1990). According to by release of CGRP, a vasodilator (Goadsby et al., 1990), 180 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187

but the mechanism of generation of pain is not clear. Studies 5.1. 5-HT1B/1D receptors in animals suggest that the pain may be caused by a sterile neurogenic inflammatory process in the dura mater (Mos- The antimigraine gold standard sumatriptan was origi- kowitz and Cutrer, 1993), but this mechanism has not been nally identified and developed based on the vasodilatory clearly demonstrated to correlate in humans (May et al., theory of migraine and the hypothesis that constriction of 1998). The pain may be a combination of an altered percep- the cerebral vascular smooth muscle would minimize the tion — as a result of peripheral or central sterilization of pain associated with migraine headache. Since the discovery craniovascular input that is not usually painful (Burstein et of sumatriptan, intensive research in this area has led to al., 2000) and the activation of feed-forward neurovascular several second generation compounds (Tables 4 and 5). dilator mechanism that is functionally specific for the first These second generation triptans, though not much different (ophthalmic) division of the trigeminal nerve (May et al., from sumatriptan in their pharmacodynamics, have 2001). improved pharmacokinetics, higher oral bioavailability and in some cases, longer plasma half-life (Slassi et al., 2001).

5. Serotonergic receptors and other pharmacological 5.2. 5-HT1F receptors targets for potential antimigraine agents Though the triptans partly exert their antimigraine Since long, it was observed that administration of 5-HT efficacy at least partly through cerebral vasoconstrictor could abort migraine attacks. Further evidence that 5-HT is effects (5-HT1B receptor mediated effect), triptans also involved in the pathophysiology of migraine was provided inhibit neurotransmitter release from trigeminal nociceptive by the observation that 5-HT metabolism in migraine neurons (Table 7). Several triptans have modest to significant patients is disturbed, interictal systemic 5-HT levels are agonist activity 5-HT1F receptors. The ability of serotonergic reduced and raised during migraine attacks, possibly a receptor agonists to inhibit plasma protein extravasation in (failing) self-defense response (Ferrari et al., 1990). These guinea pigs is correlated with their affinity to 5-HT1F observations prompted the development of sumatriptan; the receptors. In laboratory studies and preliminary clinical first migraine drug for which a specific molecular basis of studies the 5-HT1F receptor agonist LY334370 found to be action is known (Humphrey et al., 1990). Sumatriptan was efficacious in acute migraine without associated vasocon- designed to act selectively as a vasoconstrictor at 5-HT1 strictor effects observed with triptans, however subsequently receptors in cranial blood vessels, but the drug also acts on the development of LY334370 has been discontinued due to 5-HT1 receptors located in peripheral human blood vessels. poor efficacy in large trials. Further studies are warranted in The exact mode of action of sumatriptan is still under debate. order to better understand the link between 5-HT1F receptor Three distinct modes of action have been suggested and migraine with respect to clinical response to potential (Ophoff et al., 2001; Ahn and Basbaum, 2005) are 1. antimigraine therapies (Ramadan et al., 2003; Johnson et al., Vasoconstriction of meningial, dural, cerebral or pial vessels, 1998). mediated via stimulation of vascular 5-HT1B receptors. 2. Inhibition of dural neurogenic inflammation, most probably 5.3. 5-HT2B receptors mediated by presynaptic stimulation of 5-HT1D and/or 5-HT1F receptors. 3. Central inhibition of pain transmission: inhibition Recent observations suggested that gener- of trigeminal neurons in the brain stems and upper spinal cord, ation and subsequent release of inflammatory neuropeptides mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. (CGRP and substance P) from the trigeminal sensory nerve

Table 4

5-HT1B/1D receptor agonists as antimigraine agents Company Code name Generic name Trade name Formulation Novartis – Dihydroergotamine Migranal\ Nasal spray Glaxo Wellcome GR-43175 Sumatriptan Imigrain\ Imitrex Nasal spray suppository GR-85548 Naratriptan Naramig\/Amerge\ Oral AstraZeneca BW-311C-90 Zolmitriptan Zomig\ Oral Merck L705126/MK-462 Rizatriptan Maxalt\ Oral Maxalt melt Oral lysophilate Pfizer UK-116044 Eletriptan – Oral SB-209509 Vanguard VML-251 Frovatriptan – Oral Pharmacia LAS-31416 Almotriptan – Oral, sc Janssen R-91274 Alniditan – Sc Bristol-Myers Squibb BMS-180048 Avitriptan – – D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 181

Table 5 Selected pharmacologic characteristic of oral triptans

Agent Tmax during Bioavailability(%) Route of metabolism Plasma half Drug interactions/precautions migraine life (h) Naratriptan 3–4 70 CYP450 isoenzymes 6 No change in efficacy or adverse events when used with beta-blockers; efficacy not affected when used with oral contraceptives (OCs); observe patients when given with SSRIs; not contraindicated with MAO inhibitors Rizatriptan 1.0–1.5 45 MAO-A 2–3 Concomitant use with propranolol increases triptan plasma levels and requires dose adjustment; no change in efficacy or adverse events when used with metoprolol, nadolol or OCs; observe patients when given with SSRIs; contraindicated with MAO inhibitors Sumatriptan 2.5 15 2.5 Efficacy not affected when used with beta-blockers; observe patient when given with SSRIs; contraindicated with selective MAO-A and nonselective MAO inhibitors; not contraindicated with selective MAO-B inhibitors Zolmitriptan 2.5 40 CYP1A2/MAO-A 3 Concomitant use with propranolol increases plasma levels; no change in efficacy or adverse events when used with propranolol; observe patient when given with SSRIs; contraindicated with selective MAO-A and nonselective MAO inhibitors; not contraindicated with selective MAO-B inhibitors may be associated with the initiation of migraine (Johnson compounds, interpretation of their antimigraine effect in et al., 1998). Furthermore, the 5-HT2B receptors on vascular terms of blockade at this site is at present speculative. endothelial cell have been linked to NO release (Schmuck et Clinical trials with selective 5-HT7 receptor antagonists, will al., 1996). These observations coupled to the marked be awaited with interest so the potential involvement of the correlation between pharmacologically active doses of 5-HT7 receptor in migraine pathogenesis and preventive anti-migraine drugs and their potency at the human treatment is elucidated (Terron, 2002). 5-HT2B receptor (Kalkman, 1994; Fozard and Kalkman, 1994; Fozard, 1995). It has been reported that 5-HT2B 5.5. a-adrenoceptors receptors in certain vascular endothelial beds can enhance nitric oxide release, which may diffuse from the endothelial It is believed that a-adrenoceptors could be involved in cell to induce vasodilation and neuropeptide release. Thus the vascular tone of carotid circulation, which may provide the selective antagonism of 5-HT2B receptors would be a potential avenue for the development of new antimi- effective in migraine prophylaxis (Johnson et al., 1998). graine agents. It has been well established that several acutely acting antimigraine agents, including the ergots 5.4. 5-HT7 receptors (ergotamine and dihydroergotamine) produce potent vaso- constriction in the canine and porcine carotid vasculature Increasing data supports the concept that 5-HT7 receptor (De Vries et al., 1999). The canine carotid vasoconstrictor activation is responsible for the initial dilation of cerebral responses of these ergot alkaloids are mediated by 5-HT1B/ vessels and the subsequent activation of sensory pathways, 1D and a2-adrenoceptors (Villalon et al., 1999). It has been consequent to neurogenic inflammation around the menin- suggested that, the high affinity of ergotamine and gial vessels, neural sensitization and activation of pain. dihydroergotamine at a-adrenoceptors could be the possi- Potential implications of the 5-HT7 receptor in cerebrovas- ble reason for their therapeutic applications (Tfelt-Hansen cular dilation, hyperalgesia and neurogenic inflammation et al., 2000). might pave the way for new research efforts towards the understanding of migraine pathophysiological mechanism 5.6. b-adrenergic receptors and drug development. The putative involvement of this receptor in the vascular and neurogenic alteration of h-adrenoceptor blockers, the most widely used class of migraine is consistent in the concept that the condition drugs in prophylactic migraine treatment, are 60–80% may result from massive release of 5-HT after abnormal effective in producing a >50% reduction attack frequency. activation of brainstem that is secondary to the hypothala- The mechanism of action of h-adrenergic blockers is not mic dysfunctions (Fozard and Kalkman, 1994; Fozard, certain, but it appears that their anti-migraine effect is due to 1995) and the disease arises primarily from the neuro- the inhibition of h1-mediated mechanisms (Hieble, 2000). vascular interaction (May and Goadsby, 1999). Admitting, h-blockade results in inhibition of norepinephrine release by despite the fact that the correlation analysis suggest the blocking prejunctinonal h receptors. In addition, it results in 5-HT7 receptor be a target for migraine prophylactic a delayed reduction in tyrosine hydroxylase activity, the 182 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 rate-limiting step in norepinephrine synthesis, in the serotonin in the blood. Once they aggregate, platelets superior cervical ganglia. In the rat brain stem, a delayed release serotonin, and other vasoactive chemicals causing reduction of the locus ceruleus neuronal firing rate has been potent vasoconstrictive effect. Platelet aggregation has been demonstrated after propranolol administration (Hieble, shown to be altered in migraine patients and raises the 2000). This could explain the delay in the prophylactic possibility that platelet activating factor may be involved in effects of the h-blocker. the pathogenesis of migraine (Kovac et al., 1998). It is The action of h-blockers is probably central and could be demonstrated that, platelets of migraine patients showed mediated by: (i) inhibiting central h receptors interfering abnormal tendencies toward hyperaggrability and reduced with vigilance-enhancing adrenergic pathway, (ii) interac- monoamine oxidase activity. There was significant correla- tion with 5-HT receptors (but not all h-blockers bind to 5- tion in this study between MAO activity and sensitivity to HT receptors), and (iii) cross-modulation of serotonin prostaglandins (Kovac et al., 1998). Even during headache system (Ablad and Dahlof, 1986; Koella, 1985). free periods, migraine patients were shown to exhibit greater degree of platelet sensitivity to serotonin and adenosine di 5.7. Calcium channels phosphate when compared to healthy controls (Lechner et al., 1985). Urinary serotonin metabolites have been shown The complex nature of the genetics of the common to increase during the acute phase of migraine attacks. Other types of migraine has, however hampered the identification vasoactive constituents that may play a role in migraine of an underlying genetic factor. The migraine spectra include tyramine, histamine, plasmakinin, epinephrine and comprises the common types of migraine (with and norepinephrine. Many nutritional and botanical therapies without aura) as well as rate autosomal dominant variants aim to decrease platelet aggregation to inhibit the release of of migraine with aura, associated with a transient hemi- inflammatory neurotransmitters. paresis or hemiplegia (one sided weakness or paralysis of the body) in addition to other aura symptoms. In some families, symptoms of familial hemiplegic migraine are 6. Emerging therapies also associated with (progressive) permanent ataxia (dis- turbance of co-ordination of movements). The symptoms 6.1. Calciotonin gene-related peptide (CGRP) antagonists of headache and aura phase of familial hemiplegic migraine and normal migraine attacks are very similar In the recent past, there has been an upsurge in CGRP and both types may alternate within individuals and co- research and its notable role in migraine pathophysiology. occur within families. These observations suggest strongly As discussed above, migraine headache is closely associated that familial hemiplegic migraine is part of the migraine with the activation of trigeminovascular system. CGRP spectrum and that familial hemiplegic migraine can be immunoreactive fibres originating in the trigeminal ganglion used as a model to study the complex genetics of common innervate cranial cerebral blood vessels (Uddman et al., types of migraine. Importantly, familial hemiplegic mi- 1985). In animals, stimulation of these sensory nerve fibers graine exhibits a clear autosomal dominant inheritance has been shown to cause antidromic release of CGRP pattern, allowing conventional parametric linkage analysis and subsequent vasodilatation in the cerebral vasculature to identify the chromosomal localization of genes casual to (Goadsby et al., 1988; Brain and Grat, 2004). Plasma the syndrome in the specific family (Montagna, 2004; concentrations of CGRP in the jugular venous blood, but Ophoff et al., 1994, 1996). not of other neuropeptides was elevated during the headache In 50% of the familial hemiplegic migraine families, the phase of migraine (Durham, 2004a). Furthermore, in causative genes encode the brain specific voltage gated Ca2+ migraine patients: (a) strong correlation was found between channels a1A subunit (CANCNA1A) (Stilberstein and plasma CGRP concentrations and migraine headache (b) Stilberstein, 1990; Ophoff et al., 1994, 1996) located on infusion of CGRP produced a migraine-like headache (c) the short arm of chromosome 19. A number of remaining baseline CGRP levels were considerably higher and (d) the families have a locus on chromosome 1q21–q23 (Ducros et changes in plasma CGRP levels during migraine attacks al., 1997; Gardner et al., 1997), where as other familial significantly correlated with the headache intensity (Peter- hemiplegic migraine families are lined to either chromo- son et al., 2005a; Iovino et al., 2004; Durham, 2004b). some 19p or 1q (Ducros et al., 1997). These results clearly Recently Peterson et al. (2005b) has demonstrated a show a genetic heterogeneity for familial hemiplegic concentration dependent relaxation in the middle cerebral migraine with at least three different genes involved only artery when CGRP was applied abluminally, which suggest one, which has been yet identified. that CGRP mediated vasodilatation is not caused by interaction with luminally situated receptor but more likely 5.8. Platelet serotonin release by abluminal receptor on the smooth muscle cells (Fig. 1). Hence, inhibition of CGRP or antagonism of CGRP Platelets have become an important etiological consid- receptors could be a viable therapeutic target for the eration in migraine, as they contain over 90% of the pharmacological treatment of migraine (Edvinsson, 2004). D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 183

CGRP GABA (g- amino butyric acid), glutamate etc. In the central nervous system, GABA is a major inhibitory neurotrans- mitter and known anticonvulsant drugs like sodium valproate, topiramate and gabapentine have been shown to be effective in preventing migraine through modulation Adenylate cyclase of GABA neurotransmission (Cutrer, 2001; Hering and Kinitzky, 1992; Magnus, 1999).

6.3. Histamine H agonists [CAMP]i 3

In recent study, histamine H3 agonists are evaluated for PKA the safety and efficacy for migraine prophylaxis. Milan-

2+ Guerrero et al. (2003) in the first part of their study [Ca ]i determined the undesirable symptomatic effects of N-alpha-methylhistamine, a H3 receptor agonist in healthy K+ channels human volunteers and failed to identify adverse effects and in their second part of their study N-alpha-methyl hista- mine, at doses 1 and 3 Dg was found to be significantly reduced the frequency, intensity and duration of migraine Relaxation attacks as well as the need to rescue analgesics in 18 patients. Hence carefully controlled doses of H3 receptor Fig. 1. The cellular mechanisms of vasodilatation to CGRP. Activation of agonist may offer an alternative approach to migraine CGRP receptors on smooth muscle cells is coupled to production of cAMP prophylaxis. by adenylate cyclase. The increase in intracellular cAMP concentration ([cAMP]i) then stimulates protein kinase A (PKA), which opens K channels 6.4. Botulinium toxin type A and activates Ca2+ sequestration mechanisms to cause smooth muscle relation (Figure modified from Brain and Grat, 2004). BoNT-A, produced by the bacterium Clostridium botoli- nium consists of a heavy chain and light chain linked by a In line with this concept, an important breakthrough in disulfide bond. BoNT-A binds to pre-synaptic nerve terminal the field of CGRP is the development of potent CGRP receptor antagonist olcegepant (BIBN4096BS). In the in Table 6 vivo animal models of migraine, olcegepant attenuated the Drugs for migraine prophylaxis vasodilation induced by trigeminal stimulation and capsai- Preventive drugs Contraindications Indication cin-induced anastomotic dilatation (Peterson et al., 2005a; h blockers , depression, Hypertension, angina Edvinsson, 2004; Doods et al., 2000; Kapoor et al., 2000). congestive heart failure, Data from recently published clinical proof-of-concept Raynaud_s disease, diabetes study by Olesen et al. (2004) demonstrated the effectiveness Antiserotonin – Obesity, peripheral Orthostatic hypotension and safety of olcegepant for acute treatment of migraine, in Pizotifen, vascular disease which the response rate was found similar to oral triptans. methysergide No cardiovascular side effects have been reported following Ca2+-channel Constipation, Migraine with aura, administration of olcegepant. The lack of cardiovascular blockers-Verapamil hypotension hypertension, angina, asthma side effects may prove to be a major advantage for using Flunarizine Parkinson_s disease Hypertension, familial CGRP receptor antagonists to treat migraine (Durham, hemiplegic migraine 2004b). Tricyclic Mania, urinary Other pain disorders, antidepressants retention, heart block depression, anxiety 6.2. Anticonvulsants disorders, insomnia Serotonin specific Mania Depression, obsessive reuptake inhibitor compulsive disorder Migraine and share several features and respond Monoamine oxidase Glaucoma, urinary Refractory depression to many of the same pharmacological agents suggesting inhibitors retention similar mechanism may be involved in their pathophysiol- Divalproex/valproate Liver , Mania, epilepsy, ogy, hence new targets are being investigated for the bleeding disorders anxiety disorders Gabapentin Liver diseases, Mania, epilepsy, prophylactic therapy of migraine (Cutrer, 2001). Amongst bleeding disorders anxiety disorders these, anticonvulsants as a class of drugs hold promise for Topiramate Kidney stones Mania, epilepsy, the migraine prophylaxis (Table 6). These drugs are anxiety disorders thought to act through multiple mechanisms involving NSAIDS (Naproxen) Ulcer disease, gastritis Arthritis, other pain voltage gated ion channels, ligand gated ion channels, disorders 184 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 and is internalized into the cell, where it inhibits acetylcho- thus prevent migraine headaches. This belief is not without line release by interfering with vesicle docking. These effects precedence as riboflavin, in an open label study (Schoenen make BoNT-A useful for the treatment of many disorders et al., 1994) and a placebo-controlled trial (Schoenen and related to excessive muscle contraction, such as strabismus, Jacquy, 1998) has been shown to reduce migraine fre- , hemifacial spasm and cervical quency. Riboflavin is indirectly involved in the electron (Mahant et al., 2000). New applications of BoNT-A in pain transport chain as a precursor of flavin mononucleotides. therapy support a mechanism for pain reduction that is more Coenzyme Q10 is an essential element of the electron complex than a simple secondary effect of muscle relaxation. transport chain, suggesting that it could also work as BoNT-A has been used successfully to treat several different migraine preventive (Rozen et al., 2002). types of headaches, including tension type headaches (Schulte-Mattler et al., 1999), cervicogenic headaches 6.6. NK-1 receptors (Freund and Schwartz, 2000) and migraine (Brin et al., 2000). Although some types of headaches may have been According to neurogenic inflammation theory of mi- relieved by the inhibition of muscle contraction at trigger graine, SP induces dural inflammation and increases points, the efficacy of BoNT-A in treating migraine headache sensitization to migraine headache pain by stimulating implies a direct action on sensory neurons, with an indirect NK-1 receptors (Moskowitz et al., 1987). Lanepitant is a central action. It is believed that release of vasoactive high affinity, non-peptide, competitive NK-1 receptor neuropeptides, such as SP and CGRP from the trigeminal antagonist that acts both peripherally and centrally and nerve onto the vasculature produces vasodilatation and reported to be effective in guinea pig model of dural plasma protein extravasation due to increased permeability inflammation (Goldstein et al., 1999). Thus, NK-1 receptor of post capillary venules (Table 7). It is proposed that, the antagonists may have a role in migraine therapy. effectiveness of BoNT-A for the treatment of migraine in the clinical setting may be due to its inhibition of neurogenic 6.7. Nociceptin inflammation induced by the peripheral release of SP and CGRP (Cui et al., 2004). Nociceptin is an endogenous ligand for the opiate-4 (OP- 4) receptor. The OP-4 receptor abundantly expressed in 6.5. Coenzyme Q10 various CNS structures in rodents, nonhuman primates and in humans, supporting the role of nociceptin in multitude of There has been recent interest in the role that mitochon- CNS functions, including motor and balance control, dria may play in migraine pathogenesis. It is clear from the reinforcement and reward, nociception, the stress response, recent studies that at least a subset of migraineurs has a sexual behavior, aggression and autonomic control of dysfunction in mitochondrial energy metabolism. Coen- physiologic processes (Moran et al., 2000). It has been zyme Q10 is an essential element of the mitochondrial reported that approximately 70% of neurons in the human electron transport chain. It is naturally occurring, small trigeminal ganglion exhibit nociceptin immunoreactivity hydrophobic substance that freely moves throughout the and express OP-4 receptor mRNA. In these cells nociceptin membrane transferring electrons from the NADH dehydro- is co-localized with CGRP and substance P, marker peptides genase complex and the succinate-Q-reductase complex to of the trigeminovascular system. This distribution suggests cytochrome C. In addition to its actions as an electron that nociceptin may be involved in the regulation of carrier, coenzyme Q10 may act as antioxidant and help neuropeptide release from trigeminal nerve terminals and protect the myocardium from post-ischaemic reperfusion perhaps in migraine (Hou et al., 2003). Interestingly, in an injury (Frei et al., 1990; Ohhara et al., 1981). If mitochon- animal model nociceptin dose-dependently suppressed the drial dysfunction is playing a role in migraine genesis then neurogenic dural vasodilatation, while it had no effect on coenzyme Q10 could improve mitochondrial function and baseline vessel diameter (Bartsch et al., 2002), also in a recent study lower circulating levels of nociceptin was observed during migraine attacks (Ertsey et al., 2004, 2005). Table 7 Hence drugs targeting OP-4 receptor might be a promising Characteristics of serotoneric receptors involved in migraine alternative in the pharmacological treatment of migraine. Receptor Effector G protein Selective Selective agonist antagonist 6.8. Melatonin 5-HT1B Gi/Go CP 94253 GR 55562, , Adenyl GR 127935* Melatonin is a derivative of essential amino acid 5-HT cyclase GR 46611 BRL 15572 1D} tryptophan, synthesized in the pineal gland. It has wide 5-HT1F BRL 54443 – 5-HT2B jPLC Gq11 BW723C86 SB 204741 therapeutic implications including sleeping disorders, circa- 5-HT7 jAdenyl Gs AS 19 SB 269970 dian rhythm, insomnia in blind people, insomnia in elderly cyclase patients, aging and Alzheimer disease (Bubenik et al.,

*Selective 5-HT1B/1D receptor antagonist. 1998). It has been observed that some patients reporting D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 185 their headaches predominantly or specifically at a certain Bubenik, G.A., Blask, D.E., Brown, G.M., Maestroni, G.J., Pang, S.F., period of the day. Both episodic and chronic migraineurs Reiter, R.J., 1998. Prospects and clinical utilization of melatonin. Biol. Signals Recept. 7, 195–219. reported waking up in the morning with headaches or being Burstein, R., Cutrer, M.F., Yarnitsky, D., 2000. The development of woken up at night by the headache (Paiva et al., 1995). Also cutaneous allodynia during a migraine attack clinical evidence for the migraine patients without depression had lower levels of sequential recruitment of spinal and supraspinal nociceptive neurons in melatonin than controls. Since, melatonin is involved in migraine. Brain 123, 1703–1709. cerebrovascular regulation, treatment of headache disorders Cui, M., Khanijou, S., Rubino, J., Aoki, K.R., 2004. Subcutaneous administration of botulinium toxin A reduces formalin-induced pain. including migraine is promising. Melatonin may also be Pain 107, 125–133. involved in migraine comorbidity. Insomina in headache Cutrer, F.M., 2001. Antiepileptic drugs: how they work in headache. patients is the most likely associated condition in migraine Headache 41 (Suppl 1), S3–S10. to respond to melatonin therapy (Peres, 2005). However, the De Vries, P., Heiligers, J.P.C., Villalon, C.M., Saxena, P.R., 1996. Blockade data from large human trials are yet come to provide a of porcine carotid vascular response to sumatriptan by GR127935, a selective 5-HT1D receptor antagonist. Br. J. Pharmacol. 118, 85–92. proof-of-concept for the potential role of melatonin therapy De Vries, P., Sanchez-Lopez, A., Centrurion, D., Heiligers, J.P.C., Saxena, in migraine. P.R., Villalon, C.M., 1998. The canine external carotid vasoconstrictor

5-HT1 receptor: blockade by 5-HT1B (SB224289), but not by 5-HT1D (BRL15572) receptor antagonists. Eur. J. Pharmacol. 362, 69–72. De Vries, P., Willems, E.W., Heiligers, J.P., Villalon, C.M., Saxena, P.R., 7. Concluding remarks 1999. Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur. J. Pharmacol. 375, 61–74. Now the migraine research is beginning to be focused on Dimitriadou, V., Buzzi, M.G., Moskowitz, M.A., Theoharides, T.C., the development of novel agents for the acute/prophylactic 1991. Trigeminal sensory fiber stimulation induces morphological treatment like CGRP receptor antagonists, nociceptin and changes reflecting secretion in rat dura mater mast cells. Neuro- science 44, 97–112. melatonin. Thus, there is a rationale to believe that the new Dimitriadou, V., Buzzi, M.G., Theoharides, T.C., Moskowitz, M.A., 1992. class of emerging therapies will provide further information Ultrastructural evidence for neurogenically mediated changes in blood on the better understanding of molecular pathophysiology of vessels of the rat dura mater and tongue following antidromic trigeminal migraine. stimulation. Neuroscience 48, 187–203. Doods, H., Hallermayer, G., Wu, D., Entzeroth, M., Rudolf, K., Engel, W., Eberlein, W., 2000. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol. 129, Acknowledgements 420–423. Ducros, A., Joutel, A., Vahedi, K., Cecillon, M., Ferreira, A., Bernard, E., We acknowledge Dr. N. Sridhar (Center for Addiction Verier, A., Echenne, B., Lopez de Munain, A., Bousser, M.G., Tournier- and Mental Health, University of Toronto, Toronto) for his Lasserve, E., 1997. Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity. Ann. critical comments on the manuscript. We thank Dr. S. K. Neurol. 42, 885–890. Arora, (President-New Chemical Entity Research, Lupin Durham, P.L., 2004a. CGRP receptor antagonists — a fresh approach to Research Park, Pune) and Drs. S. S. Kadam and K. R. migraine therapy? N. Engl. J. Med. 350, 1073–1075. Mahadik (Bharati Vidyapeeth Deemed University, Poona Durham, P.L., 2004b. CGRP receptor antagonists: a new choice for acute College of Pharmacy, Pune) for their constant encourage- treatment of migraine? Curr. Opin. Investig. Drugs 5, 731–735. Edvinsson, L., 2004. Blockade of CGRP receptors in the intracranial ment in the work. vasculature: a new target in the treatment of migraine. Cephalalgia 24, 611–622. Ertsey, C., Hanto, M., Bozsik, G., Tekes, K., 2004. Circulating nociceptin References levels during the period. Cephalalgia 24, 280–283. Ertsey, C., Hantos, M., Bozsik, G., Tekes, K., 2005. Plasma nociceptin Ablad, B., Dahlof, C., 1986. Migraine and h-blockade: modulation of levels are reduced in migraine without aura. Cephalalgia 25, 261–266. sympathetic neurotransmission. Cephalalgia 6, 7–13. Feindel, W., Penfield, W., McNaughton, F., 1960. The tentorial nerves and Ahn, A.H., Basbaum, A.I., 2005. Where do triptan act in the treatment of localization of intracranial pain in man. 10, 555–563. migraine? Pain 115, 1–4. Ferrari, M.D., Odnik, J., Bos, K.D., Malessey, M.J.A., Bruyn, G.W., 1990. Arulmani, U., VanDenBrink, A.M., Villalon, C.M., Saxena, P.R., 2004. Neuroexcitatory plasma amino acids are elevated in migraine. Neurol- Calcitonin gene-related peptide and its role in migraine pathophysiol- ogy 40, 1582–1583. ogy. Eur. J. Pharmacol. 500, 315–330. Fozard, J.R., 1995. The 5-hydroxytryptamine-nitric oxide connection: the Bartsch, T., Akerman, S., Goadsby, P.J., 2002. The ORL-1 (NOP(1) key link in the initiation of migraine? Arch. Int. Pharmacodyn. Ther. receptor ligand nociceptin/orphanin FQ (/OFQ) inhibits neurogenic 329, 111–119. dural vasodilatation in the rat. Neuropharmacology 43, 991–998. Fozard, J.R., Kalkman, H.O., 1994. 5-Hydroxytryptamine (5-HT) and the Brain, S.D., Grat, A.D., 2004. Vascular actions of calicitonin gene-related initiation of migriane: new perspectives. Naunyn-Schmiedeberg’s Arch. peptide and adrenomedullin. Physiol. Rev. 84, 903–934. Pharmacol. 350, 225–229. Brain, S.D., Williams, T.J., 1985. Inflammatory oedema induced by Frei, B., Kim, M.C., Ames, B.N., 1990. Ubiquinol-10 is an effective lipid synergism between calcitonin gene-related peptide (CGRP) and media- soluble antioxidant at physiological concentrations. Proc. Natl. Acad. tors of increased vascular permeability. Br. J. Pharmacol. 86, 855–860. Sci. U. S. A. 87, 4879–4883. Brin, M.F., Swope, D.M., O’Brien, C., Abbasi, S., Pogoda, J.M., 2000. Freund, B.J., Schwartz, M., 2000. Treatment of chronic cervical- Botox for migraine: double blind, placebo-controlled, region-specific associated headache with botulinium toxin A: a pilot study. Headache evaluation. Cephalalgia 20, 421–422. 40, 231–236. 186 D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187

Gardner, K., Barmada, M.M., Ptacek, L.J., Hoffman, E.P., 1997. A new Launer, L.J., Terwindt, G.M., Ferrari, M.D., 1999. The prevalence and locus for hemiplegic migraine maps to chromosome 1q31. Neurology characteristics of migraine in a population-based cohort: the GEM 49, 1231–1238. study. Neurology 53, 537–542. Goadsby, P.J., 2001. Migraine: selecting treatments now and making Lechner, H., Ott, E., Fazekas, F., Pilger, E., 1985. Evidence of enhance requests for the future? Curr. Med. Res. Opin. 17, S98–S99. platelet aggregation and platelet sensitivity in migraine patients. Goadsby, P.J., Hoskin, K.L., 1997. The distribution of trigeminovascular Cephalalgia 5, 89–91. afferents in the nonhuman primate brain Macaca nemestrina: a c-fos Liption, R.B., Bigal, M.E., 2005. The epidemiology of migraine. Am. J. immunocytochemical study. J. Anat. 190, 367–375. Med. 118, S3–S10. Goadsby, P.J., Edvinsson, L., Ekman, R., 1988. Release of vasoactive Lipton, R.B., Bigal, M.E., Scher, A.I., Stewart, W.F., 2003. The global peptides in the extracerebral circulation of humans and the cat during burden of migraine. J. Headaches Pain 4, S3–S11. activation of the trigeminovascular systems. Ann. Neurol. 23, 193–196. Magnus, L., 1999. Nonepileptic use of gabapentine. Epilepsia 40, S66–S72. Goadsby, P.J., Edvinsson, L., Ekman, R., 1990. Release of vasocactive Mahant, N., Clouston, P.D., Lorentz, I.T., 2000. The current use of peptides in the extracerebral circulation of humans and the cat during botulinium toxin. J. Clin. Neurosci. 7, 389–394. activation of the trigeminal system. Ann. Neurol. 23, 193–196. Martin, P.R., Milech, D., Nathan, P.R., 1993. Towards a functional model of Goldstein, D.J., Offen, W.W., Klein, E.G., Phebus, L.A., 1999. Lanepitant, chronic headaches: investigation of antecedents and consequences. an NK-1 antagonist, in migraine. Cephalalgia 19, 377. Headache 33, 461–470. Graham, J.R., Wolf, H.G., 1938. Mechanism of migraine headache and May, A., Goadsby, P.J., 1999. The trigeminovascular system in humans: action of ergotamine tartrate. Arch. Neurol. Psychiatry 39, 737–763. pathophysiological implications for primary headache syndromes of Hering, R., Kinitzky, A., 1992. Sodium valproate in the prophylactic neural influences on the cerebral circulation. J. Cereb. Blood Flow treatment of migraine. A double blind study versus placebo. Cepha- Metab. 19, 115–127. lalgia 12, 81–84. May, A., Shepheard, S.L., Knorr, M., Effert, R., Wessing, A., Hargreaves, Hieble, J.P., 2000. Adrenoceptor subclassification: an approach to improved R.J., Goadsby, P.J., Diener, H.C., 1998. Retinal plasma extravasation in cardiovascular therapeutics. Pharm. Acta Helv. 74, 163–171. animals but not in humans: implications for the pathophysiology of Hoskin, K.L., Zagami, A.S., Goadsby, P.J., 1999. Stimulation of the migraine. Brain 121, 1231–1237. middle meningeal artery leads to Fos expression in the trigeminocer- May, A., Buchel, C., Turner, R., Goadsby, P.J., 2001. Magnetic resonance vical nucleus: a comparative study of monkey and cat. J. Anat. 194, angiography in facial and other pain: neurovascular mechanisms of 579–588. trigeminal sensation. J. Cereb. Blood Flow Metab. 21, 1171–1176. Hou, M., Uddman, R., Tajti, J., Edvinsson, L., 2003. Nociceptin Menken, M., Munsat, T.L., Toole, J.F., 2000. The global burden of disease iuumnoreactivity and receptor mRNA in the human trigeminal study: implications for neurology. Arch. Neurol. 57, 418–420. ganglion. Brain Res. 964, 179–186. Michel, P., Henry, P., Letenneur, L., Jogeix, M., Corson, A., Dartigues, J.F., Humphrey, P.P., Feniuk, W., Perren, M.J., 1990. Anti-migraine drugs in 1993. Diagnostic screen for assessment of the IHS criteria for migraine development: advances in serotonin receptor pharmacology. Headache by general practitioners. Cephalalgia 13 (Suppl 12), 54–59. 30 (Suppl. 1), 12–16. Milan-Guerrero, R.O., Pineda-Lucatero, A.G., Hernanadez-Benjamin, T., International Headache Society, 2004. International classification of head- Tene, C.E., Pacheco, M.F., 2003. Naptha-methylhistamine. Safety and ache disorders. Cephalalgia 24 (Sup.1), 1–160. efficacy in migraine prophylaxis: phase I and phase II studies. Headache Iovino, M., Feifel, U., Young, C.L., Wolters, J.M., Wallenstein, G., 2004. 43, 389–394. Safety, tolerability, and pharmacokinetics of BIBN 4096 BS, the first Montagna, P., 2004. The physiopathology of migraine: the contribution of selective small molecule calcitonin gene-related peptide receptor genetics. Neurol. Sci. 25, S93–S96. antagonist, following single intravenous administration in health Moran, T.D., Abdulla, F.A., Smith, P.A., 2000. Cellular neurophysiological volunteers. Cephalalgia 24, 645–656. actions of nociceptin/orphan FQ. Peptides 21, 969–976. Johnson, K.W., Phebus, L.A., Cohen, M.L., 1998. Serotonin in migraine: Moskowitz, M.A., 1990. Basic mechanisms in vascular headache. Neurol. theories, animal models and emerging therapies. Prog. Drug Res. 51, Clin. 8, 801–815. 219–244. Moskowitz, M.A., 1992. Trigeminovascular system. Cephalalgia 12, 127.

Kalkman, H.O., 1994. Is migraine prophylactic activity caused by 5-HT2B Moskowitz, M.A., 1993. Neurogenic inflammation in the pathophysiology or 5-HT2C receptor blockade? Life Sci. 54, 641–644. and treatment of migraine. Neurology 43, S16–S20. Kapoor, K., Arulmani, U., Heiligers, J.P., Garrelds, I.M., Willems, E.W., Moskowitz, M.A., Cutrer, F.M., 1993. Sumatriptan: a receptor-targeted Doods, H., Villalon, C.M., Saxena, P.R., 2000. Effects of the CGRP treatment for migraine. Annu. Rev. Med. 44, 145–154. receptor antagonist BIBN4096BS on induced carotid Moskowitz, S., Saito, K., Moskowitz, M.A., 1987. Neurogenically haemodynamic changes in anaesthetised pigs. Br. J. Pharmacol. 140, mediated leakage of plasma protein occurs from blood vessels in dura 329–338. mater but not in brain. J. Neurosci. 7, 4129–4136. Kerr, F.W., 1960. Atypical facial neuralgias: their mechanism as inferred Ohhara, H., Kanaide, H., Yoshimura, R., Okada, M., Nakamura, M., 1981. from anatomic and physiologic data. Mayo Clin. Proc. 36, 254–260. A protective effect of coenzyme Q10 on ischemia and reperfusion of the Koella, W.P., 1985. CNS-related (side) effects of h-blockers with special isolated perfused rat heart. J. Mol. Cell. 13, 65–74. reference mechanisms of action. Eur. J. Clin. Pharmacol. 28, 55–63. Olesen, J., Lipton, R.B., 1994. Migraine classification and diagnosis. Kovac, K., Tothfaulsi, L., Herman, F., Magyar, K., 1998. MAO activity, International Headache Society criteria. Neurology 44, S6–S10. serotonin metabolism and aggregation of platelets from migraine Olesen, J., Tfelt-Hansen, P., Henriksen, L., Larsen, B., 1981. The common patients. A preliminary study. Pol. J. Pharmacol. Pharm. 40, 691–695. migraine attack may not be initiated by cerebral ischaemia. Lancet 2, Lance, J.W., 2000. Headache and face pain. Med. J. Aust. 172, 450–455. 438–440. Lance, J.W., Lambert, G.A., Goadsby, P.J., Duckworth, J.W., 1983. Olesen, J., Diener, H., Husstedt, I.W., Goadsby, P.J., Hall, D., Meier, U., Brainstem influences on the cephalic circulation: experimental data Pollentier, S., Lesko, L.M., 2004. Calcitonin gene-related peptide from cat and monkey of relevance to the mechanism of migraine. receptor antagonist BIBN 4096 BS for the acute treatment of migraine. Headache 23, 258–265. N. Engl. J. Med. 350, 1104–1110. Lashley, K.S., 1941. Patterns of cerebral integration indicated by the Ophoff, R.A., van Eijk, R., Sandkuijl, L.A., Terwindt, G.M., Grubben, C.P., scotomas of migraine. Arch. Neurol. 46, 331–339. Haan, J., Lindhout, D., Ferrari, M.D., Frants, R.R., 1994. Genetic Lashley, J., Larsen, B., Lauritzen, M., 1981. Related focal hyperemia heterogeneity of familial hemiplegic migraine. Genomics 22, 21–26. followed by spreading oligemia and impaired activation of rCBF in Ophoff, R.A., Terwindt, G.M., Vergouwe, M.N., van Eijk, R., Oefner, P.J., classic migraine. Ann. Neurol. 9, 344–352. Hoffman, S.M., Lamerdin, J.E., Mohrenweiser, H.W., Bulman, D.E., D.K. Arulmozhi et al. / Vascular Pharmacology 43 (2005) 176–187 187

Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.J., Hofker, M.H., Schoenen, J., Lenaerts, M., Bastings, E., 1994. High dose riboflavin as a Ferrari, M.D., Frants, R.R., 1996. Familial hemiplegic migraine and prophylactic treatment of migraine: results of an open label pilot study. episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene Cephalalgia 14, 328–329. CACNL1A4. Cell 87, 543–552. Schulte-Mattler, W.J., Wieser, T., Zierz, S., 1999. Treatment of tension Ophoff, R.A., van den Maagdenberg, A.M., Roon, K.I., Ferrari, M.D., type headache with botulinium toxin: a pilot study. Eur. J. Med. Res. Frants, R.R., 2001. The impact of pharmacogenetics for migraine. Eur. 4, 183–186. J. Pharmacol. 9, 1–10. Silberstein, S.D., 2004. Migraine. Lancet 363, 381–391. Paiva, T., Batista, A., Martins, A., 1995. The relationship between Slassi, A., Isaac, M., Arora, J., 2001. Novel serotonergic and non- headaches and sleep disturbances. Headache 35, 590–596. serotonergic migraine headache therapies. Expert Opin. Ther. Pat. 11, Pearce, J.M., 1984. Migraine: a cerebral disorder. Lancet 14, 86–89. 625–649. Peres, M.F.P., 2005. Melatonin, the pineal gland and their implications for Stilberstein, S.D., Stilberstein, M.M., 1990. New concepts in the patho- headache disorders. Cephalalgia 25, 403–411. genesis of headache: Part II. Pain Manage. 3, 334–342.

Peterson, K.A., Lassen, L.H., Birk, S., Lesko, L., Olesen, J., 2005a. Terron, J.A., 2002. Is the 5-HT7 receptor involved in the pathogenesis BIBN4096BS antagonizes human a-calcitonin gene related peptide- and prophylactic treatment of migraine? Eur. J. Pharmacol. 439, induced headache and extracerebral artery dilatation. Clin. Pharmacol. 1–11. Ther. 77, 202–213. Terwindt, G.M., Ophoff, R.A., van Eijk, R., Vergouwe, M.N., Haan, J., Peterson, K.A., Nilsson, E., Olesen, J., Edvinsson, L., 2005b. Presence and Frants, R.R., Sandkuijl, L.A., Ferrari, M.D., Dutch Migraine Genetics function of the calcitonin gene-related peptide receptor on rat pial Research Group, 2001. Involvement of the CACNA1A gene containing arteries investigated in vitro and in vivo. Cephalalgia 25, 424–432. region on 19p13 in migraine with and without aura. Neurology 56, Ramadan, N.M., Skljarevski, V., Phebus, L.A., Johnson, K.W., 2003. 1028–1032. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Tfelt-Hansen, P., Saxena, P.R., Dahlof, C., Pascual, J., Lainez, M., Henry, Cephalalagia 23, 776–785. P., Diener, H., Schoenen, J., Ferrari, M.D., Goadsby, P.J., 2000. Rasmussen, B.K., Olesen, J., 1992. Migraine with aura and migraine Ergotamine in the acute treatment of migraine: a review and European without aura: an epidemiological study. Cephalalgia 12, 221–228. consensus. Brain 123, 9–18. Rasmussen, B.K., Jensen, R., Schroll, M., Olesen, J., 1992. Interrelations Uddman, R., Edvinsn, L., Ekman, R., Kingman, T., McCulloch, J., 1985. between migraine and tension-type headache in the general population. Innervation of the feline cerebral vasculature by nerve fibers containing Arch. Neurol. 49, 914–918. calcitonin-gene-related peptide: trigeminal orgin and co-existence with Rozen, T.D., Oshinsky, M.L., Gebeline, C.A., Bradely, K.C., Young, W.B., substance P. Neurosci. Lett. 62, 131–136. Silberstein, S.D., 2002. Open label trial of coenzyme Q10 as a migraine Villalon, C.M., De Vries, P., Rabelo, G., Centrurion, D., Sanchez-Lopez, preventive. Cephalalgia 22, 137–141. A., Saxena, P.R., 1999. Canine external carotid vasoconstriction to

Schmuck, K., Ullmer, C., Kalkman, H.O., Probst, A., Lubbert, H., 1996. methysergide, ergotmine and dihydroergotamine: a role of 5-HT1B/1D Activation of meningeal 5-HT2B receptors: an early step in the receptors and a-adrenoceptors. Br. J. Pharmacol. 1265, 385–394. generation of migraine headache? Eur. J. Neurosci. 8, 959–967. Willems, E.W., Valdivia, L.F., Villalon, C.M., Saxena, P.R., 2003. Possible Schoenen, J., Jacquy, L.M., 1998. Effectiveness of high-dose riboflavin in role of a-adrenoceptor subtypes in acute migraine therapy. Cephalalgia migraine prophylaxis. A randomized controlled trial. Neurology 50, 23, 245–257. 466–470.