Experimental models of migraine

Handbook of Clinical Neurology, Vol. 97 (3rd series) Headache G. Nappi and M.A. Moskowitz, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 8

Experimental models of migraine M.G. BUZZI 1 AND C. TASSORELLI 2 * Headache Center, IRCCS Santa Lucia Foundation, Rome, Italy 2 Headache Science Center, IRCCS “C. Mondino Institute of Neurology” Foundation and University Center for the Study of Adaptive Disorders and Headache (UCADH), University of Pavia, Pavia, Italy 1

INTRODUCTION In the past two decades, the availability of animal models of migraine has allowed impressive advances in understanding the mechanisms and mediators underlying migraine attacks, as well as the development of new and more specific therapeutic agents. The trigeminovascular system (TVS) has emerged as a critical efferent component, and the mediators of its activity have been identified and characterized, as have some of the receptors involved. Studies involving substances known to induce migraine-like attacks have provided interesting insights into the central nuclei probably involved in the initiation and recurrence of migraine attacks. Furthermore, new molecules, potentially effective in migraine treatment, have been screened and tested in the different experimental models so far available and, having given satisfactory results, are now in the pipeline to become commercially available antimigraine drugs (Figure 8.1). Over the years, animal models of several types have been devised, proposed, tested, and used. These models are listed in a schematic classification in Table 8.1 (for review see also Bergerot et al., 2006).

VASCULAR MODELS In vitro Isolated cranial (meningeal, temporal, basilar) and coronary arteries of animals are used as in vitro models of migraine to characterize the receptors in these blood vessels and to study the effects of potential antimigraine molecules. However, it should be borne in mind that a species that is a good model for a certain class of drugs

*

may be less suitable for studying other receptor systems. Blood vessels can be studied using anatomical, physiological, and pharmacological methods and studies are needed to confirm which species provides the best model.

ISOLATED

ANIMAL VESSELS

Vascular segments obtained from several species are mounted in organ baths and contraction or relaxation is measured isometrically. Construction of cumulative concentration response curves is used to determine the potency (pEC50) and efficacy (Emax) of a potential antimigraine agent. Experiments in endothelium-denuded blood vessels provide information on the localization of the receptor, while measurements of second messengers or intracellular calcium concentrations (Ishida et al., 2001) may provide information on the receptors involved. The role of endogenous neuropeptides in perivascular nerve endings was investigated in artery segments stimulated chemically (Franco-Cereceda et al., 1987) or electrically to release calcitonin gene-related peptide (CGRP) and other neuropeptides. CGRP receptors have been studied in blood vessels obtained from several species, including the pig, guinea pig, and rat (Jansen-Olesen et al., 2001; Wu et al., 2002). Instead, bovine cerebral arteries (Bouchelet et al., 2000; Roon et al., 2000) and the dog or rabbit saphenous vein have frequently been used to study contractile responses to the triptans.

ISOLATED

HUMAN VESSELS

The therapeutic efficacy of antimigraine drugs is probably mediated by constriction of dilated cranial arteries (Saxena and Tfelt-Hansen, 2005). Models of isolated cranial blood vessels use three cranial arteries: the

Correspondence to: Cristina Tassorelli, Headache Science Center, IRCCS “C. Mondino Institute of Neurology” Foundation and University Center for the Study of Adaptive Disorders and Headache (UCADH), University of Pavia, Pavia, Italy, Tel: þ39(0)382-380425, Fax: þ39(0)382-380448, E-mail: [email protected]

110

M.G. BUZZI AND C. TASSORELLI Advantages

Fig. 8.1. Virtuous cycle connecting experimental models of migraine with advances in understanding based on the disease pathophysiology and treatment and with improvement of the models themselves.

middle meningeal, the basilar, and the temporal. The human middle meningeal artery, in particular, is richly innervated with afferent sensory fibers containing substance P (SP), neurokinin A (NKA), and CGRP originating from the trigeminal ganglion. The rank order of potency of serotonin (5-HT) receptor agonists in this preparation positively correlates with affinity measurements in cell lines expressing the 5-HT1B receptor. Human isolated coronary arteries are used to test the effect of antimigraine drugs on vascular beds other than the cerebral one. The right epicardial coronary artery is the most commonly used segment in isolated coronary blood vessel models.

Isolated cerebral blood vessel models offer several advantages, i.e. they make it possible to localize the receptor involved, to investigate the role of endogenous neuropeptides, to measure second messengers or intracellular calcium concentrations, and to evaluate the role of endogenous neuropeptides in perivascular nerve endings. In addition, studies of in vitro human models allow the assessment of receptorial cranial selectivity and the collection of reliable information regarding the behavior of these vessels in migraine headache. In particular, denudation of the cranial arteries provides information on whether the receptors are present on the endothelium or in the vascular smooth muscle of arteries. Furthermore, isolated human coronary arteries are useful in analyzing a major potential side-effect of antimigraine drugs, namely chest symptoms (chest pressure, tightness, and pain). Limitations These in vitro models study drug–receptor interactions at equilibrium without the influence of pharmacokinetic factors, central and autonomic mechanisms, or circulating hormones. In addition, they cannot reflect the complexity of the mechanisms underlying migraine pathophysiology.

Table 8.1 Animal models of migraine Type of model

Investigated structure or function

Vascular (vasoconstriction or vasodilatation) In vitro Isolated arteries and veins In vivo

Carotid arterial bed, arteriovenous anastomoses, pial arteries

Neurovascular Plasma protein extravasation (PPE)

Trigeminovascular system

Activation of trigeminal nucleus caudalis (TNC)

Trigeminovascular system Central nociceptive pathways

Cortical spreading depression

Vasodilatation and activation of trigeminal neurons by spreading depression Trigeminovascular system Central nociceptive pathways Autonomic–nociceptive interaction

Effects of nitric oxide donors

(Reproduced from Bergerot et al., 2006.)

Methodology

Effects of drugs, modulation of electrical stimulation Evaluation of vascular resistance, measurement of diameter Induction or inhibition of PPE by electrical or chemical stimulation of the ganglion and evaluation of PPE with dyes or radiolabeled tracers Meningeal stimulation or electrical/ mechanical stimulation of the superior sagittal sinus Cortical application of potassium chloride solutions, Fos expression in TNC Neurochemical, cerebrovascular, and nociceptive response to systemic or central administration of nitroglycerine

EXPERIMENTAL MODELS OF MIGRAINE

In vivo In vivo vascular animal models are developed to mimic cranial vasodilatation as an integral part of the pathophysiology of migraine and they are based on vascular or neurogenic theories (De Vries et al., 1999a). The species most frequently used in these models are pigs and dogs.

CONSTRICTION

OF CAROTID ARTERIOVENOUS

ANASTOMOSES IN ANAESTHETIZED PIGS AND OF THE CANINE EXTERNAL CAROTID BED

Arteriovenous anastomoses are precapillary communications between the arteries and veins; they are predominantly located in the scalp, ears, nasal mucosa, eyes, and dura mater in several species, including humans and pigs (Saxena, 1995). It has been shown that several acutely acting antimigraine drugs, including ergot alkaloids and triptans, constrict porcine carotid arteriovenous anastomoses and that a dilatation of these “shunt” vessels may be involved in the pathophysiology of migraine (Heyck, 1969; Saxena, 1995; De Vries et al., 1996, 1999a). Indeed, opening of the carotid arteriovenous anastomoses during a migraine attack might cause a large quantity of oxygenated blood to be shunted directly into the veins, resulting in facial pallor, a lowering of skin temperature, and an increase in vascular pulsations (Saxena, 1995). This increase in vascular pulsations stimulates the so-called stretch receptors located in the blood vessel walls, which in turn activate peptide-containing perivascular trigeminal nerves (e.g., CGRP) (De Vries et al., 1999a; Villalo´n et al., 2002). Radioactive microspheres are used to measure the carotid arteriovenous anastomotic blood flow and the effects of drugs on this parameter (De Vries et al., 1999b). Similar to the porcine model is the model of constriction of the canine external carotid bed (De Vries et al., 1999a). This model has proven its merit over the years and has been highly predictive of antimigraine activity in the clinical setting. Advantages The major advantage of these models is that one can simultaneously study different vascular beds in order to evaluate the cranioselectivity of antimigraine drugs (De Vries et al., 1999b; Willems et al., 2003). All acutely active antimigraine agents, including ergot alkaloids and triptans, as well as a-adrenoceptor agonists, potently constrict the porcine carotid bed and the corresponding arteriovenous anastomoses (De Vries et al., 1996, 1999b; Willems et al., 1999). These agents also provoke long-lasting vasoconstriction in the canine external carotid bed (Saxena and de

111

Vlaam-Schluter, 1974), although the pharmacological profile of this effect is very complex (Hoyer et al., 1994) and involves subtype-selective a-adrenoceptors (Willems et al., 2003). Limitations Although highly predictive of antimigraine activity, these experimental models will only pick up the activity of potential antimigraine drugs that act via vascular mechanisms.

INTRAVITAL

MICROSCOPY

Intravital microscopy makes it possible to study the peripheral branch of the TVS. This model uses a thinned closed cranial window and video microscopy to visualize cranial, dural, and pial blood vessels, and allows measurement of changes in their diameter (Williamson et al., 1997a, b). The cranial window is covered with mineral oil (37  C) and a branch of the middle meningeal artery is viewed using an intravital microscope, with the image displayed on a television monitor. Electrical stimulation of the cranial window causes a reproducible dural and pial blood vessel dilatation, which involves activation of the trigeminal nerve, via the release of CGRP from presynaptic trigeminal nerve endings (Williamson et al., 1997a; Akerman et al., 2002; Petersen et al., 2004). Similarly, CGRP and nitric oxide (NO), when used in intravital microscopy, are able to cause reproducible dural blood vessel dilatation (Akerman et al., 2002), and therefore the model acts as a direct correlate of the migraine attack. Triptans, 5-HT1B/1D receptor agonists, dihydroergotamine, and CGRP receptor antagonists (administered intravenously) are capable of inhibiting neurogenic dural vasodilatation (Williamson et al., 1997a; Petersen et al., 2004). Other compounds found to inhibit neurogenic dural vasodilatation, and useful in antimigraine therapy, are neuronal NO synthase (NOS) inhibitors and indomethacin, a non-steroidal anti-inflammatory drug (Akerman et al., 2002). Also, cannabinoid CB1 receptor agonists (Akerman et al., 2004), P/Q-, N-, and L-type voltage-dependent calcium channel blockers (Akerman et al., 2003), nociceptin (Bartsch et al., 2002), and adenosine A1 receptor agonists (Honey et al., 2000) were tested in this model and emerged as potential targets in the clinic.

MENINGEAL BLOOD FLOW DOPPLER FLOWMETRY

STUDIES USING LASER

Laser Doppler flowmetry uses changes in blood flow as an indirect measure of vessel diameter. Measurements of meningeal blood flow via laser Doppler flowmetry have also proved successful in predicting antimigraine efficacy. This model was a precursor to the intravital

112

M.G. BUZZI AND C. TASSORELLI

microscopy method for directly measuring changes in dural meningeal blood vessels as an output of trigeminovascular activation, but using an open cranial window. Indeed, some methodologies have combined the two strategies to measure both meningeal and cerebral changes (Petersen et al., 2004). Electrical stimulation of dural sites causes a reproducible increase in meningeal blood flow (Kurosawa et al., 1995; Messlinger et al., 1997), and these changes are attenuated by 5-HT1 receptor agonists and abolished by a CGRP receptor antagonist (Kurosawa et al., 1995; Messlinger et al., 1997). Advantages The intravital microscopy models not only help us to identify compounds that may have therapeutic value in the clinic, but are also able to help us dissect the pharmacology of the TVS, and therefore the mechanisms underlying migraine and the actions of therapeutic compounds. In addition, these models provide information about the tolerability profile of drugs and the anatomy and physiopathology of cortical spreading depression (CSD). The intravital microscopy models directly measure dural vessels rather than measuring blood flow via laser Doppler flowmetry, and measurement of dural vessel diameter may be more relevant to the mechanisms of migraine pain than measurement of dural blood flow. Measurements of meningeal blood flow via laser Doppler flowmetry were able to predict compounds with a lack of clinical efficacy and have also assisted in dissecting the pharmacology of meningeal nociception and the TVS. Limitations Direct measurement of dural vessel diameter gives a direct measure of vasodilatation, while blood flow measurements are complicated by a number of factors, including blood cell velocity, cell concentration, and perfusion pressure, and increases in flow may not be due to vasodilatation alone.

NEUROVASCULAR MODELS The neurogenic model of migraine implies that any stimulus that depolarizes trigeminal sensory fibers activates the TVS and induces blood flow changes in intra- and extracranial tissues receiving trigeminal innervation (Moskowitz, 1984). The trigeminal pain pathway, as related to migraine, is comprised of three main sites: (1) the trigeminal cells in the ganglion with their projections to the vessels (TVS) and to the brainstem; (2) the trigeminal nucleus caudalis (TNC) in the

brainstem; and (3) the brain as the site of pain consciousness. Each of these sites has been suggested to play an essential role in migraine pathophysiology. Neurogenic inflammation (vasodilatation and plasma protein extravasation) within cephalic tissues has been proposed as a possible mechanism of headache pathogenesis (Mayberg et al., 1984; Moskowitz, 1984). The main mediators of neurogenic inflammation are SP (Lembeck and Holzer, 1979), NKA, and CGRP, which are released upon depolarization of sensory fibers innervating blood vessels (Saria et al., 1985, 1986). Tachykinin (SP and NKA) receptors are located on the endothelium to mediate endothelium-dependent vasodilatation and increased permeability, whereas receptors located on vascular smooth muscle mediate CGRP-induced vasodilatation. The dura mater is an important source of headache pain (Ray and Wolff, 1940), provides a thick covering for the brain, and contains blood vessels with fenestrated capillary endothelium (Andres et al., 1987). The dura and its attendant blood vessels are innervated by trigeminal and upper sensory nerve fibers which contain the vasoactive peptides (SP, NKA, and CGRP) (Edvinsson and Uddman, 1982; Mayberg et al., 1984; Jansen et al., 1986). Small perivascular unmyelinated C fibers reside within the adventitial layer and upon depolarization they release the above peptides to produce neurogenic plasma extravasation.

Activation and modulation of the trigeminovascular system TRIGEMINAL

STIMULATION AND PLASMA PROTEIN

EXTRAVASATION

Plasma protein extravasation can be elicited in the rat dura mater by unilateral electrical trigeminal ganglion stimulation (UETGS) or chemical stimulation. UETGS has been performed in rats (Markowitz et al., 1987) by means of stereotactic lowering of a bipolar electrode in the trigeminal ganglion through which an electrical stimulus was delivered at a magnitude of 1.2 mA, 5 Hz, for 5 min. Radiolabeled albumin, given intravenously prior to stimulation, served to detect the amount of plasma extravasation following the stimulus. Dura mater from the stimulated side and from the non-stimulated side were compared to detect differences in plasma protein leakage, according to counts of leaked radioactive albumin. Protein leakage also occurred in extracranial tissues (conjunctiva, eyelid, lip, and tongue) receiving trigeminal innervation (Buzzi and Moskowitz, 1990). Following UETGS, plasma protein leakage was observed in the dura mater on light microscopy by means of intravenous injection of horseradish peroxidase (HRP), which usually binds to plasma protein and

EXPERIMENTAL MODELS OF MIGRAINE can be visualized as an electron-dense HRP reaction product (Buzzi et al., 1992). Evans blue dye was concomitantly administered along with active tracers, in order to confirm the correct location of the electrode (by enhancing the blue color of the skin on the stimulated side). The effects of the antimigraine drugs, ergot derivatives and sumatriptan, were tested in this model and were found to block protein leakage effectively (Buzzi and Moskowitz, 1990). In order to verify whether their effect was mediated by vasoconstriction, ergot alkaloids and sumatriptan were tested in rats in conditions of exogenous SP-induced protein leakage and vasodilatation (Buzzi and Moskowitz, 1990). Leakage was not blocked and a mechanism of action mediated by prejunctional receptors for ergots and sumatriptan has been postulated in this model (Buzzi and Moskowitz, 1990). Pharmacological data (Humphrey et al., 1988) suggested that a 5-HT receptor subtype mediates the effects of sumatriptan in the UETGS model. Results obtained by using different 5-HT agonists and antagonists in the same experimental setting proved that the effects of sumatriptan were highly consistent with a 5-HT1B/D-mediated activity (Buzzi et al., 1991). Activation of trigeminal sensory fibers innervating cephalic blood vessels has also been obtained by systemic administration of capsaicin (the pungent ingredient of hot pepper) and plasma protein leakage detected, as described above, in rat dura mater, eyelid, and lip of capsaicin-stimulated versus non-stimulated animals (Markowitz et al., 1987; Saito et al., 1988; Buzzi and Moskowitz, 1990). Degranulation of mast cells accompanies the plasma leakage response in the dura mater following UETGS (Dimitriadou et al., 1991), and contributes to the inflammatory reaction in this tissue during migraine attacks (Waeber and Moskowitz, 2005; Levy et al., 2006). Mast cell degranulation was inhibited by sumatriptan (Buzzi et al, 1992). A stimulation intensity-dependent increase in CGRP plasma levels was observed during UETGS in the venous blood obtained from the superior

113

sagittal sinus (SSS) (Buzzi et al., 1991). Sumatriptan reduced this CGRP increase, confirming the activity of the drug on prejunctional receptors on trigeminal sensory fibers. The latter observation is in agreement with the increase of CGRP plasma levels in the cat following trigeminal ganglion stimulation, and in blood obtained from the jugular vein of humans during migraine attacks (Goadsby and Edvinsson, 1993). CGRP levels fell in humans following sumatriptan administration, and the migraine pain improved as well (Goadsby and Edvinsson, 1993). Peripheral activation of trigeminal fibers is reflected in the modulation of cells receiving primary afferent inputs. As demonstrated by Nishimori and co-workers (1989), UETGS increases preproenkephalin expression in laminae I and II of the ipsilateral TNC (Figure 8.2).

CHEMICAL

STIMULATION OF THE MENINGES

Subarachnoid hemorrhage is one of the most predictable and dramatic causes of vascular headaches (Wolff, 1972). The pain is thought to be attributable, to a large degree, to sensitization and stimulation of perivascular afferents and to reflect increased neurotransmission within sensory fibers projecting to cephalic blood vessels (Moskowitz et al., 1989). Subarachnoid hemorrhage alters levels of tachykinins and mRNA in trigeminal ganglia and in perivascular axons (Linnik et al., 1989). SP levels increase in the trigeminal ganglion 2 days after intravenous injection. Accordingly, preprotachykinin mRNA, encoding for the peptide, increases in the trigeminal ganglion. SP increases in the trigeminal ganglion may reflect compensation for the depletion occurring in perivascular fibers. Direct stimulation of primary sensory neurons supplying the meninges has been obtained through injection of meningeal irritants via microcatheter into the cisterna magna through the atlantooccipital membrane of anesthetized rats (Mitsikostas et al., 1998), mice

Fig. 8.2. Samples of rat dura mater obtained from the side ipsilateral to unilateral electrical trigeminal ganglion stimulation (right) and from the unstimulated side (left) after intravenous injection of horseradish peroxidase (HRP). HRP leakage from vessels is due to increased permeability following trigeminal fiber depolarization. (Reproduced from Buzzi et al., 1992.)

114

M.G. BUZZI AND C. TASSORELLI

(Mitsikostas et al., 2002), and guinea pigs (Cutrer et al., 1999). Meningeal irritants include autologous blood (Linnik et al., 1989; Nozaki et al., 1992a), capsaicin (Mitsikostas et al., 1998), and carrageenin (Nozaki et al., 1992b). Fos protein immunoreactivity in both sides of the TNC is detected 2 h after injection. Capsaicin induces Fos protein expression in a dose-dependent manner (Mitsikostas et al., 1998), and the response is inhibited by destruction of unmyelinated fibers (Nozaki et al., 1992a). This experimental setting has limitations due to the lack of intra-animal control – it is not possible to explore lateralization of Fos protein expression within the TNC – and also due to possible damage caused by capsaicin that may alter the blood–brain barrier functioning, leading to indirect activation of central sites (Mitsikostas and Sanchez del Rio, 2001).

decahydroisoquinoline-3-carboxylic acid) both inhibit Fos expression in this model of trigeminovascular activation (Classey et al., 2001; Filla et al., 2002), implicating their receptor systems in the pathophysiology of migraine.

STIMULATION

Limitations

OF THE SUPERIOR SAGITTAL SINUS

The SSS is one of the sources of cephalic pain. Indeed, stimulation of this structure in humans produces pain referred to the head (Ray and Wolff, 1940). Therefore, stimulation of the SSS in animals has been considered a possible experimental model for evaluating mechanisms underlying head pain. SSS stimulation has been performed in rats, cats (Kaube et al., 1993), and nonhuman primates (Goadsby and Hoskin, 1999) in order to study trigeminovascular nociceptive afferents. Electrical stimulation of the pain-producing structures of the head, including the SSS, as well as chemical and electrical stimulation of trigeminal sensory fibers (see above), are established methods of trigeminovascular activation and they have been widely used to investigate the activation of neurons, reflected in increased Fos expression (see also paragraph on Fos expression) in the TNC following trigeminal ganglion, dural or SSS stimulation in the cat, and to evaluate the effects, on Fos, of a variety of compounds. 5-HT1B/1D receptor agonists zolmitriptan (Goadsby and Hoskin, 1998) and eletriptan (Goadsby and Hoskin, 1999; Knyiha´r-Csillik et al., 2000) have both been shown to reduce Fos immunoreactivity in the trigeminocervical complex, whereas the less lipophilic sumatriptan was unable to reduce Fos expression (Goadsby and Hoskin, 1999) unless the blood–brain barrier was disrupted (Kaube et al., 1993). In vivo pretreatment with CP93,129, sumatriptan, or dihydroergotamine inhibits Fos expression in the TNC induced by subarachnoid hemorrhage (Moskowitz and Macfarlane, 1993). Taken together, this evidence suggests a peripheral as well as central site of action for the triptans, a hypothesis that has now been definitively confirmed. The antagonists of the N-methyl-D-aspartate receptor (MK-801) and the GluR5 kainate receptor ([3S,4aR,6S,8aR]-6-[4-carboxyimidazol-1-ylmethyl]

Advantages The neurogenic inflammation model in animals has provided a simple and reproducible experimental setting for testing the effects of different compounds on the peripheral and central components of cephalic pain. This was the case, for instance of CGRP antagonists (Storer et al., 2004). The similarity of the trigeminal innervation across species has made it possible to draw conclusions on the neurophysiological responses to electrical or chemical stimulation of the trigeminal fibers (for review see Goadsby et al., 2009).

The lack of an adequate experimental human model of induced neurogenic inflammation and the likely species differences in receptor subtypes are the main limitations preventing us from establishing the full clinical relevance of the data obtained from animal studies.

FOS

EXPRESSION WITHIN THE TRIGEMINAL NUCLEUS

CAUDALIS AS A MARKER OF TRIGEMINAL NOCICEPTION

Fos protein is used as a marker of nociception and of neuronal activation. It is known that a peripheral noxious stimulation induces Fos immunoreactivity within laminae I and II of the spinal dorsal horns (Williams et al., 1990). Fos expression within the TNC may be induced by applying mechanical, electrical, or chemical stimuli to either extracranial or intracranial tissues innervated by the trigeminal nerve (e.g., SSS stimulation, chemical stimulation of the meninges, and trigeminal ganglion stimulation). Thus, Fos immunoreactivity offers a method for identifying subpopulations of neurons activated in response to noxious stimuli, or other types of stimuli that may be relevant to migraine (Tassorelli and Joseph, 1995), and the relative nociceptive pathways. Expression of the gene can be measured via Northern blot analysis (Ashmawi et al., 2003) or with in situ hybridization (Nakagawa et al., 2003), while the protein expression is usually visualized by means of immunocytochemical techniques (Benjamin et al., 2004). Advantages Studies based on the evaluation of c-fos gene activation have provided information on the neuroanatomy of the structures that may be involved in migraine pathophysiology, the timing of their activation, as well as on possible modulation of this activation by pharmacological probes.

EXPERIMENTAL MODELS OF MIGRAINE 115 areas develops with a latency of hours, contrasts with Limitations the very short plasma half-life of the drug, although Fos immunhistochemistry provides information on this longer latency may be a consequence of NTG metabolically activated pathways, but not on circuits accumulation in the brain (Torfga˚rd et al., 1991). that may be inhibited by a given stimulus. In addition, Reuter et al. (2001) demonstrated that NTG administraabsence of Fos expression does not necessarily mean tion induces an up-regulation of proinflammatory that the neuronal population was not activated; it may genes, with a subsequent, delayed inflammatory reacsimply mean that the c-fos pathways were not activated tion in the dura mater of the rat. Intravenous NTG by the stimulus. increases NO production within macrophages of dura mater with a delay of hours, via the expression of the NITRIC OXIDE DONORS inducible isoform of NOS (iNOS) (Reuter et al., 2001, Nitric oxide (NO) plays a pivotal role in the control of 2002). iNOS expression is preceded by a significant several physiological phenomena in the central nervous increase in the activity of nuclear factor kappa B system, such as nociception, toxicity, degeneration, (NF-kB), a transcription factor that is crucial for and memory. NO donors have been used as probes to inflammation reaction (Reuter et al., 2002). study the role of NO in a variety of neurological Co-localization studies have shown that NTGdiseases (Rayman et al., 2003; Kakizawa et al., 2007). induced neuronal activation takes place in adrenergic, A relationship between NO and migraine has been sugnitrergic and neuropeptidergic structures (Tassorelli gested since headaches are a side-effect of NO donors et al., 1999), indicating some of the possible signaling (Iversen and Olesen, 1996). pathways involved in the phenomenon. NeuropharmacoNitrovasodilators, in view of their vasodilatory logic manipulations have suggested that NTG-induced effect, were originally used in the treatment of ischemic neuronal activation probably involves exogenous cardiac disease (Parker et al., 1995) to produce NO in (NTG-derived) NO that might act directly at both the several body tissues (including the brain). This has vascular and neuronal levels, or indirectly activate neufavored a resurgence of scientific interest in this group rovascular responses via multiple pathways (Greco of substances in the field of the neurosciences. Among et al., 2005; Tassorelli et al., 2007). Previous data support the various nitrovasodilators commercially available, the idea that cyclic guanosine monophosphate is an nitroglycerine (NTG) is a classic NO donor that acts as important mediator of the NTG effect in vascular and trigger or provoking agent in cluster headache (Ekbom, neuronal structures (Tassorelli et al., 2004), however 1968). Furthermore, infusion of NTG leads to a migraine recently it was shown that NTG administration is capable attack in migraineurs with a latency of 4–6 h (Iversen of activating the cyclooxygenase-2 pathway within cereet al., 1989; Olesen et al., 1994; Sances et al., 2004) bral areas of the rat, explaining the pronociceptive effect and inhibition of NOS has antimigraine activity (Lassen of NTG described in animal and human models of pain et al., 2003). There exists experimental evidence of an (Tassorelli et al., 2000, 2003, 2007). accumulation of NTG in the rat brain tissue, since Indeed, Tassorelli et al. (2003) have shown that the NO donor is highly lipophilic and easily crosses the NTG-induced changes in central and/or peripheral blood–brain barrier (Torfga˚rd et al., 1991). Systemic neurotransmission are related to a hyperalgesic state administration of this organic nitrate induces, in the and this is reflected in the sustained activation of rat, neuronal activation in several brain nuclei belonging nociceptive nuclei in the rat (Tassorelli and Joseph, to the neurovegetative, neuroendocrine, behavioral, and 1995). This explanation could also account for the nociceptive systems (such as the TNC) (Tassorelli initiation of a spontaneous migraine-like attack in and Joseph, 1995; Tassorelli et al., 1997). predisposed subjects following NTG administration The precise mechanisms involved in NO-triggered (Iversen et al., 1989; Sances et al., 2004). This hypothmigraine remain to be determined. The temporal proesis has also been supported by other findings file of neuronal activation following NTG administraobtained by other groups, which strongly suggest a tion shows that neuronal activation begins as early as definite role for NTG in pain mediation. Pardutz 60 min postinjection in brain areas that control the caret al. (2000) showed that NTG administration diovascular function, and reaches its maximum expresincreases the number of NOS-immunoreactive cells sion 3 h later in nociceptive and integrative structures in the rat spinal TNC, which points to the activation (Tassorelli et al., 1997). This modulated temporal of second-order neurons through a presynaptic excitacourse suggests a dual mechanism of action for NTG tory mechanism. Lambert et al. (2000) demonstrated on the brain: an initial effect on the vascular comthat systemic NTG increases the firing rate of secpartment followed by the involvement of integrativeond-order trigeminal neurons, which transport inputs nociceptive structures. This activation, which in some from cranial structures via a serotonin-mediated

116

M.G. BUZZI AND C. TASSORELLI

3 V

A

and Martin, 2001; Offenhauser et al., 2005) failed to detect NTG-induced Fos expression in the TNC. However, several possible variables must be carefully controlled when using NTG-based animal models to study the TVS: (1) the drug dose and modality of administration; (2) the drug-dissolving vehicle; (3) the chosen observation time; and (4) systems for administration of the drug. In studies where Fos expression was not detected in the rat, doses of NTG similar to those in human migraine studies were used (0.2–2 g/kg intravenously). In studies in which NTG-induced Fos expression was consistently noted, higher doses of NTG were given subcutaneously. Finally, as regards the issue of the duration of observations, it must be noted that, in order to be relevant to migraine, the effects of NTG infusion in studies using this technique will need to be observed for several hours in order to reflect the timing of the development of migraine attacks (Iversen et al., 1989).

CORTICAL

B Fig. 8.3. Photomicrographs illustrating the activation induced by nitroglycerine in the paraventricular (A) and supraoptic (B) nuclei of the hypothalamus. The blue staining (nicotinamide adenine dinucleotide phosphate: NADPH) indicates neurons containing nitric oxide synthase. Fos immunoreactivity appears as brown-stained round or ovoid-shaped nuclei. Filled arrowheads point to examples of neurons double-labeled for both neuronal markers, whereas neurons expressing only Fos or NADPH-d activity are indicated by empty arrowheads and arrows, respectively. Scale bar: 60 mm. 3V, third ventricle. (Reproduced from Tassorelli et al., 1999.)

mechanism that is blocked by the administration of selective 5-HT1B/1D agonists (Figure 8.3). Advantages The data obtained using the animal methods based on the administration of NO donors have yielded an increasing body of evidence for a better understanding of migraine pathophysiology. In addition, they have provided information on potential new targets for antimigraine drugs (Greco et al., 2009; Va`mos et al., 2009). Areas of controversy There is some controversy, in the literature, with regard to the neurochemical effects of NTG. For instance, some investigators (Jones et al., 2001; Martin

SPREADING DEPRESSION

Lea˜o’s (1944) hypothesis that CSD could play a role in migraine has become very credible. Functional magnetic resonance imaging data from the human visual cortex provide strong evidence that CSD underlies migraine visual aura (Hadjikhani et al., 2001), and a similar phenomenon may underlie migraine auras emanating from other brain regions. CSD can be induced in animals by chemical (superfusion with potassium chloride solution), pinprick, or electrical stimulation over the cortex surface. A reduction in the threshold for the induction of CSD has been demonstrated in female mice compared with male mice (Brennan et al., 2007; Figure 8.4). CSD provokes the expression of Fos protein-like immunoreactivity within neurons of the TNC via trigeminovascular mechanisms (Moskowitz et al., 1993). c-fos gene activation following unilateral spreading depression is inhibited both by sumatriptan and trigeminal denervation, suggesting a role for peripheral fibers in this model and their involvement in the mechanism of action of the drugs (Moskowitz et al., 1993). CSD induces long-lasting blood flow enhancement within the middle meningeal artery, consistent with the consequences of a noxious stimulus within the trigeminal receptive field (Bolay et al., 2002). Vasodilatation is caused by the release of vasoactive agents from parasympathetic projections originating from parasympathetic nuclei of cranial nerve VII. Parasympathetic neurons are activated by monosynaptic connections with the TNC. CSD also causes plasma protein leakage into the ipsilateral dura mater

EXPERIMENTAL MODELS OF MIGRAINE

117

FP

Stim

A

18 s.

35 s.

58 s.

150 s.

300 s.

Field Potential (mV)

Reflectance (R/R0*100)

B

C

100

90

80

0

−10

0

10 Time (min.)

Fig. 8.4. Optical intrinsic signal imaging of cortical spreading depression (CSD) in mice. B shows the propagation of CSD, while C shows the time course of the optical signal and the field potential changes, from a region of interest immediately adjacent to the field potential electrode. FP: field potential. (Reproduced from Brennan et al., 2007.)

(Bolay et al., 2002). As detailed above, protein extravasation is mediated via release of proinflammatory peptides from trigeminal axon collaterals innervating the meninges. This finding supports the complex neuronal-neurovascular model of the migraine attack. Meningeal inflammation persists after CSD subsides, an observation which suggests that intense and transient brain activity can cause sustained meningeal events and C-fiber discharge.

Advantages The demonstration that CSD is a mechanism underlying neurovascular events is of great interest since it creates a link between cortical and peripheral components and opens up the way for the development of adequate preventive therapies that may act centrally as inhibitors of migraine episodes. The ability of preventive therapies commonly used in the prophylaxis of migraine without aura to suppress CSD

118

M.G. BUZZI AND C. TASSORELLI

events in animal models (Ayata et al., 2006) also suggests that migraine with aura and migraine without aura may be different manifestations of the same disorder.

noxious stimuli are perceived as noxious in sensitized tissues. All the above data support the notion of peripheral and central sensitization during migraine attacks (Burstein, 2001).

Limitations

Advantages

It remains to be elucidated whether silent aura events occur in migraine without aura and where they take place, prior to the activation of the peripheral component of the pain.

The recognition of sensitization phenomena in migraine patients may contribute to the development of targeted therapies: not only early treatments for migraine attacks, but also the development of compounds able to prevent the evolution of episodic forms of migraine into chronic pain.

CENTRAL

PAIN SENSITIZATION AND THE

TRIGEMINAL NERVE

The theory of chemical activation of meningeal perivascular sensory fibers suggests that ions, protons, and inflammatory agents that activate and sensitize peripheral nociceptors are released in the vicinity of sensory fibers innervating the dura after an episode of CSD or neurogenic inflammation. Exposure of perivascular fibers to chemical agents alters their sensitivity to mechanical stimuli and leads to the sensitization observed in head pain. Application of acidic and inflammatory agents to the dura enabled peripheral fibers innervating the dura (Strassman et al., 1996) to respond to mechanical stimuli that had initially evoked minimal or no response. This phenomenon may explain the hypersensitivity of migraine patients to normally induced changes in intracranial pressure, as in bending or coughing. This hypothesis has been tested in the rat by recording changes in the responsiveness of dura-sensitive neurons in the TNC to mechanical stimulation of their dural receptive fields and to mechanical or thermal stimulation of their cutaneous receptive fields after local application of inflammatory mediators or acid agents to the dura (Burstein et al., 1998). Brief chemical stimulation induced significantly increased sensitivity to mechanical indentation of the dura as well as increased cutaneous mechanosensitivity and thermosensitivity. The role of a central mechanism has been suggested in this model, since local application of lidocaine to the dura abolished the response to dural stimulation but not to cutaneous stimulation. According to these findings, chemical activation and sensitization of dura-sensitive peripheral nociceptors could lead to enhanced responses in central neurons, and central sensitization could therefore result in extracranial tenderness in the absence of extracranial pathology. In subsequent studies (Yamamura et al., 1998), it has been demonstrated that non-noxious stimuli in sensitized dura induce cardiovascular responses, at a magnitude similar to that observed following noxious stimuli, thus confirming that non-

Limitations In order to develop targeted drugs that may reduce the risk of chronic pain, detailed neurophysiology and functional neuroimaging investigations are needed to demonstrate the presence of sensitization in the dura mater and central nuclei in humans.

GENETIC FACTORS AND MIGRAINE Genetic factors play an important role in migraine pathophysiology (Kors et al., 2004), probably by lowering the threshold for migraine. Familial hemiplegic migraine (FHM) is an autosomal-dominant subtype of migraine with aura. Apart from the characteristic hemiparesis, typical attacks of FHM are identical to those of the common forms of migraine. This rare and severe form of migraine has been associated with three different mutations identified in three genes encoding subunits of a calcium channel (CACNA1A), a sodium-potassium pump (ATP1A2) and a sodium channel (SCN1A) (Ophoff et al., 1996; De Fusco et al., 2003; Dichgans et al., 2005). The CACNA1A gene (FHM1) encodes the pore-forming a1-subunit of voltage-gated neuronal Cav2.1 (P/Q-type) Ca2þ channels; the ATP1A2 gene (FHM2) encodes the a2-subunit of Naþ-Kþ pumps, while the SCN1A gene (FHM3) encodes the a1-subunit of neuronal sodium channels. Missense mutations of CACNA1A cause an increased open probability of P/Q-type calcium channels and a shift of the activation voltage range towards depolarization (Tottene et al., 2002) with an increased glutamate release in cortical neurons. Fifteen different missense mutations in the CACNA1A gene have been associated with FHM. Although the consequences of CACNA1A gene mutations on trigeminal nociception remain undocumented, one can predict that the gain-of-function of calcium channels at synaptic level may lead to hyperexcitability of nociceptive trigeminovascular pathways due to enhanced release of vasoactive

EXPERIMENTAL MODELS OF MIGRAINE neuropeptides from perivascular nerve endings and, possibly, facilitation of sensitization of second-order central trigeminal neurons. In fact, within the TVS, P/Q-type channels, together with N-type channels, control CGRP release from capsaicin-sensitive trigeminovascular afferents (Hong et al., 1999). Some mutations cause pure FHM, whereas other mutations may cause FHM plus additional neurological symptoms such as ataxia or coma (Ducros et al., 2001). Mutations in ATP1A2 result in either a loss of Na-K pump function or a reduced affinity of potassium for Na-K pumps (De Fusco et al., 2003; Segall et al., 2004). Consequently, extracellular Kþ levels might be expected to be higher in ATP1A2. FHM3 mutations in the SCN1A gene cause a more rapid recovery from fast inactivation of neuronal Nav1.1 sodium channels after depolarization. Because these sodium channels are crucial for the generation and propagation of action potentials, FHM3 mutations are likely to cause an increased frequency of neuronal firing and enhanced neuronal excitability and neurotransmitter release (Dichgans et al., 2005).

Genetic models CACNA1A

MOUSE MODELS

Several mouse CACNA1A mutants, either natural or transgenic, are available, most of them with variable symptoms of ataxia and epilepsy. The most promising CACNA1A model for migraine mechanisms is a recently generated knock-in (KI) mouse model carrying the human FHM1 R192Q mutation in the endogenous CACNA1A gene (van den Maagdenberg et al., 2004). Unlike the other CACNA1A mice, R192Q KI mice do not exhibit any overt phenotype. The results in R192Q KI mice may explain the mechanism underlying the increased susceptibility of the migraine brain to aura and reinforce the hypothesis that migraine is associated with neuronal hyperexcitability at cortical and, possibly, brainstem level (van den Maagdenberg et al., 2004). It has been reported that mutated Cav2.1 channels allow increased calcium influx and cause more neurotransmitter release. This might, in turn, be associated with transient neuronal hyperexcitability. Cav2.1 channels can best be studied in their native neuronal environment at their endogenous level of expression, evaluating how they affect mechanisms involved in migraine such as neurotransmission and CSD. Cav2.1 channels are expressed in all brain structures that have been implicated in the pathogenesis of migraine, including the cerebral cortex, the trigeminal ganglia, and brainstem nuclei involved in the central control of nociception (Pietrobon and Striessnig, 2003).

ATP1A2

119

MOUSE MODELS

Transgenic mice in which the ATP1A2 (FHM2) gene was abolished (ATP1A2-null mutants) have been generated, but they die immediately after birth because they cannot breathe spontaneously (Ikeda et al., 2003). Heterozygous ATP1A2þ/– mice revealed enhanced fear and anxiety behaviors after conditioned fear stimuli, probably due to neuronal hyperactivity in the amygdala and piriform cortex (Ikeda et al., 2003). Therefore, these mice do not, as yet, seem to provide an adequate substrate for learning more about the role of the described FHM ATP1A2 mutation in the pathogenesis of migraine.

ACKNOWLEDGMENT The authors are grateful to Dr Rosaria Greco for her support in the preparation of the manuscript.

REFERENCES Akerman S, Williamson DJ, Kaube H et al. (2002). Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol 137: 62–68. Akerman S, Kaube H, Goadsby PJ (2003). Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation. Br J Pharmacol 140: 718–724. Akerman S, Kaube H, Goadsby PJ (2004). Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol 142: 1354–1360. Andres KH, von Du¨ring M, Muszinsky K et al. (1987). Nerve fibers and their terminals of the dura mater encephali of the rat. Anat Embryol (Berl) 175: 289–301. Ashmawi HA, Chambergo FS, Arau´jo Palmeira CC et al. (2003). The effects of pyrilamine and cimetidine on mrna c-fos expression and nociceptive flinching behavior in rats. Anesth Analg 97: 541–546. Ayata C, Jin H, Kudo C et al. (2006). Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol 59: 652–661. Bartsch T, Akerman S, Goadsby PJ (2002). The ORL-1 (NOP1) receptor ligand nociceptin/orphanin FQ (N/ OFQ) inhibits neurogenic dural vasodilatation in the rat. Neuropharmacology 43: 991–998. Benjamin L, Levy MJ, Lasalandra MP et al. (2004). Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis 16: 500–505. Bergerot A, Holland PR, Akerman S et al. (2006). Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci 24: 1517–1534. Bolay H, Reuter U, Dunn AK et al. (2002). Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8: 136–142.

120

M.G. BUZZI AND C. TASSORELLI

Bouchelet I, Case B, Olivier A et al. (2000). No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Br J Pharmacol 129: 501–508. Brennan KC, Romero Reyes M, Lo´pez Valde´s HE et al. (2007). Reduced threshold for cortical spreading depression in female mice. Ann Neurol 61: 603–606. Burstein R (2001). Deconstructing migraine headache into peripheral and central sensitization. Pain 89: 107–110. Burstein R, Yamamura H, Malick A et al. (1998). Chemical stimulation of the intracranial dura induces enhanced response to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 79: 964–982. Buzzi MG, Moskowitz MA (1990). The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 99: 202–206. Buzzi MG, Carter WB, Shimizu T et al. (1991). Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 30: 1193–1200. Buzzi MG, Dimitriadou V, Theoharides TC et al. (1992). 5Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res 583: 137–149. Classey JD, Knight E, Goadsby PJ (2001). The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res 907: 117–124. Cutrer FM, Mitsikostas DD, Ayata G et al. (1999). Attenuation by butalbital of capsaicin-induced c-fos-like immunoreactivity in trigeminal nucleus caudalis. Headache 39: 697–704. De Fusco M, Marconi R, Silvestri L et al. (2003). Haploinsufficiency of ATP1A2 encoding the Naþ/Kþ pump a2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33: 192–196. De Vries P, Heiligers JC, Villalo´n CM et al. (1996). Blockade of porcine carotid vascular response to sumatriptan by GR 127935, a selective 5-HT1D receptor antagonist. Br J Pharmacol 118: 85–92. De Vries P, Villalo´n CM, Saxena PR (1999a). Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol 375: 61–74. De Vries P, Villalo´n CM, Saxena PR (1999b). Pharmacology of triptans. Emerg Drugs 4: 107–125. Dichgans M, Freilinger T, Eckstein G et al. (2005). Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 336: 371–377. Dimitriadou V, Buzzi MG, Moskowitz MA et al. (1991). Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells. Neuroscience 44: 97–112. Ducros A, Denier C, Joutel A et al. (2001). The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 345: 17–24.

Edvinsson L, Uddman R (1982). Immunohistochemical localization and dilatatory effect of substance P on human cerebral vessels. Brain Res 232: 466–471. Ekbom K (1968). Nitrolglycerin as a provocative agent in cluster headache. Arch Neurol 19: 487–493. Filla SA, Winter MA, Johnson KW et al. (2002). Ethyl (3S,4ar,6S,8ar))6-(4-ethoxycarbonylimidazol)1-ylmethyl) decahydroiso-quinoline)3-carboxylic ester: a prodrug of a GluR5 kainate receptor antagonist active in two animal models of acute migraine. J Med Chem 45: 4383–4386. Franco-Cereceda A, Rudehill A, Lundberg JM (1987). Calcitonin gene-related peptide but not substance P mimics capsaicin-induced coronary vasodilation in the pig. Eur J Pharmacol 142: 235–243. Goadsby PJ, Edvinsson L (1993). The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33: 48–56. Goadsby PJ, Hoskin KL (1998). Serotonin inhibits trigeminal nucleus activity evoked by craniovascular stimulation through a 5HT1B/1D receptor: a central action in migraine. Ann Neurol 43: 711–718. Goadsby PJ, Hoskin KL (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. Goadsby PJ, Charbit AR, Andreou AP et al. (2009). Neuroscience forefront review – Neurobiology of migraine. Neuroscience 161 (2009) 327–341. Greco R, Tassorelli C, Cappelletti D et al. (2005). Activation of the transcription factor NF-kappaB in the nucleus trigeminalis caudalis in an animal model of migraine. Neurotoxicology 26: 795–800. Greco R, Gasperi V, Sandrini G et al. (2009). Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia 2009 [Epub ahead of print]. Hadjikhani N, Sanchez Del Rio M, Wu O et al. (2001). Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 98: 4687–4692. Heyck H (1969). Pathogenesis of migraine. Res Clin Stud Headache 2: 1–28. Honey AC, Bland-Ward PA, Connor HE et al. (2000). Study of an adenosine A1 receptor agonist on trigeminally evoked dural blood vessel dilation in the anaesthetized rat. Cephalalgia 22: 260–264. Hong KW, Kim CD, Rhim BY et al. (1999). Effect of omega-conotoxin GVIA and omega-agatoxin IVA on the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial arteries. J Cereb Blood Flow Metab 19: 53–60. Hoyer D, Clarke DE, Fozard JR et al. (1994). International Union of Pharmacology classification of receptors for 5 hydroxytryptamine (serotonin). Pharmacol Rev 46: 157–203. Humphrey PP, Feniuk W, Perren MJ et al. (1988). GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein. Br J Pharmacol 94: 1123–1132.

EXPERIMENTAL MODELS OF MIGRAINE Ikeda K, Onaka T, Yamakado M et al. (2003). Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (ATP1A2)-deficient mice. J Neurosci 23: 4667–4676. Ishida A, Murray J, Saito C et al. (2001). Expression of vascular endothelial growth factor receptors in smooth muscle cells. J Cell Physiol 188: 359–368. Iversen HK, Olesen J (1996). Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs. Cephalalgia 16: 412–418. Iversen HK, Olesen J, Tfelt-Hansen P (1989). Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38: 17–24. Jansen I, Uddman R, Hocherman M et al. (1986). Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries. Ann Neurol 20: 496–501. Jansen-Olesen I, Kaarill L, Edvinsson L (2001). Characterization of CGRP (1) receptors in the guinea pig basilar artery. Eur J Pharmacol 414: 249–258. Jones MG, Lever I, Bingham S et al. (2001). Nitric oxide potentiates response of trigeminal neurones to dural or facial stimulation in the rat. Cephalalgia 21: 643–655. Kakizawa H, Matsui F, Tokita Y et al. (2007). Neuroprotective effect of nipradilol, an NO donor, on hypoxicischemic brain injury of neonatal rats. Early Hum Dev 83: 535–540. Kaube H, Hoskin KL, Goadsby PJ (1993). Inhibition by sumatriptan of central trigeminal neurones only after blood–brain barrier disruption. Br J Pharmacol 109: 788–792. Knyiha´r-Csillik E, Tajti J, Csillik AE et al. (2000). Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion, and on the expression of c-fos and c-jun in the trigeminal complex of the rat in an experimental migraine model. Eur J Neurosci 12: 3991–4002. Kors EE, Vanmolkot KR, Haan J et al. (2004). Recent findings in headache genetics. Curr Opin Neurol 17: 283–288. Kurosawa M, Messlinger K, Pawlak M et al. (1995). Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin generelated peptide. Br J Pharmacol 114: 1397–1402. Lambert GA, Donaldson C, Boers PM et al. (2000). Activation of trigeminovascular neurons by glyceryl trinitrate. Brain Res 887: 203–210. Lassen LH, Christiansen I, Iversen HK et al. (2003). The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs. Cephalalgia 23: 877–886. Leao AA (1944). Spreading depression of activity in the cerebral cortex. J Neurophysiol 7: 359–390. Lembeck F, Holzer P (1979). Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn Schmiedebergs Arch Pharmacol 310: 175–183.

121

Levy D, Burstein R, Strassman AM (2006). Mast cell involvement in the pathophysiology of migraine headache: a hypothesis. Headache 46: S13–S18. Linnik MD, Sakas DE, Uhl GR et al. (1989). Subarachnoid blood and headache: altered trigeminal tachykinin gene expression. Ann Neurol 25: 179–184. Markowitz S, Saito K, Moskowitz MA (1987). Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci 7: 4129–4136. Martin RS, Martin GR (2001). Investigations into migraine pathogenesis: time course for effects of m-CPP, BW723C86 or glyceryl trinitrate on appearance of Foslike immunoreactivity in rat trigeminal nucleus caudalis (TNC). Cephalalgia 21: 46–52. Mayberg MR, Zervas NT, Moskowitz MA (1984). Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry. Comp Neurol 223: 46–56. Messlinger K, Hotta H, Pawlak M et al. (1997). Effects of the 5-HT1 receptor agonists, sumatriptan and CP 93,129, on dural arterial flow in the rat. Eur J Pharmacol 332: 173–181. Mitsikostas DD, Sanchez del Rio M (2001). Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Rev 35: 20–35. Mitsikostas DD, Sanchez del Rio M, Waeber C et al. (1998). The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 76: 239–248. Mitsikostas DD, Sanchez del Rio M, Waeber C (2002). 5-Hydroxytryptamine (1B/1D) and 5-hydroxytryptamine1f receptors inhibit capsaicin-induced c-fos immunoreactivity within mouse trigeminal nucleus caudalis. Cephalalgia 22: 384–394. Moskowitz MA (1984). The neurobiology of vascular head pain. Ann Neurol 16: 157–168. Moskowitz MA, Macfarlane R (1993). Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 5: 159–177. Moskowitz MA, Buzzi MG, Sakas DE et al. (1989). Pain mechanisms underlying vascular headaches. Progress report 1988. Rev Neurol (Paris) 145: 181–193. Moskowitz MA, Nozaki K, Kraig RP (1993). Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 13: 1167–1177. Nakagawa T, Katsuya A, Tanimoto S et al. (2003). Differential patterns of c-fos mrna expression in the amygdaloid nuclei induced by chemical somatic and visceral noxious stimuli in rats. Neurosci Lett 344: 197–200. Nishimori T, Buzzi MG, Moskowitz MA et al. (1989). Preproenkephalin mrna expression in nucleus caudalis neurons is enhanced by trigeminal stimulation. Brain Res Mol Brain Res 6: 203–210.

122

M.G. BUZZI AND C. TASSORELLI

Nozaki K, Boccalini P, Moskowitz MA (1992a). Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. Neuroscience 49: 669–680. Nozaki K, Moskowitz MA, Boccalini P (1992b). CP-93,129, sumatriptan, dihydroergotamine block c-fos expression within the rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges. Br J Pharmacol 106: 409–415. Offenhauser N, Zinck T, Hoffmann J et al. (2005). CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 25: 225–236. Olesen J, Thomsen LL, Iversen H (1994). Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci 15: 149–153. Ophoff RA, Terwindt GM, Vergouwe MN et al. (1996). Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Cell 87: 543–552. Pardutz A, Krizbai I, Multon S et al. (2000). Systemic nitroglycerin increases nnos levels in rat trigeminal nucleus caudalis. Neuroreport 11: 3071–3075. Parker JO, Amies MH, Hawkinson RW et al. (1995). Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group. Circulation 91: 1368–1374. Petersen KA, Birk S, Doods H et al. (2004). Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat. Br J Pharmacol 143: 697–704. Pietrobon D, Striessnig J (2003). Neurobiology of migraine. Nat Rev Neurosci 4: 386–398. Ray BS, Wolff HG (1940). Experimental studies on headache. Pain sensitive structures of the head and their significance in headache. Arch Surg 41: 813–856. Rayman G, Baker NR, Krishnan ST (2003). Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care 26: 2697–2698. Reuter U, Bolay H, Jansen-Olesen I et al. (2001). Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124: 2490–2502. Reuter U, Chiarugi A, Bolay H et al. (2002). Nuclear factorkappab as a molecular target for migraine therapy. Ann Neurol 51: 507–516. Roon KI, Olesen J, Diener HC 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. Saito K, Markowitz M, Moskowitz MA (1988). Ergot alkaloids block neurogenic extravasation in dura mater: proposed action in vascular headache. Ann Neurol 24: 732–737. Sances G, Tassorelli C, Pucci E et al. (2004). Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia 24: 110–119.

Saria A, Ma RC, Dun NJ (1985). Neurokinin A depolarizes neurons of the guinea pig inferior mesenteric ganglia. Neurosci Lett 60: 145–150. Saria A, Gamse R, Petermann J et al. (1986). Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices. Neurosci Lett 63: 310–314. Saxena PR (1995). Cranial arteriovenous shunting, an in vivo animal model for migraine. In: J Olesen, MA Moskowitz (Eds.), Experimental Headache Models, Vol. 27. Lippincott-Raven, Philadelphia, pp. 189–198. Saxena PR, de Vlaam-Schluter GM (1974). Role of some biogenic substances in migraine and relevant mechanism in antimigraine action of ergotamine – studies in an experimental model for migraine. Headache 3: 142–163. Saxena PR, Tfelt-Hansen P (2005). Triptans, 5-HT1B/1D receptor agonists in the acute treatment of migraine. In: J Olesen, PJ Goadsby, N Ramadan et al. (Eds.), The Headaches. Lippincott Williams & Wilkins, Philadelphia, pp. 469–503. Segall L, Scanzano R, Kaunisto MA et al. (2004). Kinetic alterations due to a missense mutation in the Na,K-atpase alpha2 subunit cause familial hemiplegic migraine type 2. J Biol Chem 279: 43692–43696. Storer RJ, Akerman S, Goadsby PJ (2004). Calcitonin generelated peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 142: 1171–1181. Strassman AM, Raymond SA, Burstein R (1996). Sensitization of meningeal sensory neurons and the origin of headache. Nature 384: 560–564. Tassorelli C, Joseph SA (1995). Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 682: 167–181. Tassorelli C, Joseph SA, Nappi G (1997). Neurochemical mechanisms of nitroglycerin-induced neuronal activation in rat brain: a pharmacological investigation. Neuropharmacology 36: 1417–1424. Tassorelli C, Joseph SA, Buzzi MG et al. (1999). The effects on the central nervous system of nitroglycerin – putative mechanisms and mediators. Prog Neurobiol 57: 607–624. Tassorelli C, Costa A, Blandini F et al. (2000). Effect of nitric oxide donors on the central nervous system nitroglycerin studies in the rat. Funct Neurol 15: 19–27. Tassorelli C, Greco R, Wang D et al. (2003). Nitroglycerin induces hyperalgesia in rats – a time-course study. Eur J Pharmacol 464: 159–162. Tassorelli C, Blandini F, Greco R et al. (2004). Nitroglycerin enhances cgmp expression in specific neuronal and cerebrovascular structures of the rat brain. J Chem Neuroanat 27: 23–32. Tassorelli C, Greco R, Armentero MT et al. (2007). A role for brain cyclooxygenase-2 and prostaglandin-E2 in migraine: effects of nitroglycerin. Int Rev Neurobiol 82: 373–382. Torfga˚rd K, Ahlner J, Axelsson KL et al. (1991). Tissue levels of glyceryl trinitrate and cgmp after in vivo administration in rat, and the effect of tolerance development. Can J Physiol Pharmacol 69: 1257–1261.

EXPERIMENTAL MODELS OF MIGRAINE Tottene A, Fellin T, Pagnutti S et al. (2002). Familial hemiplegic migraine mutations increase Ca(2þ) influx through single human cav2.1 channels and decrease maximal cav2.1 current density in neurons. Proc Natl Acad Sci U S A 99: 13284–13289. Va`mos E, Fejes A, Koch J et al. (2009). Kynurenate Derivative Attenuates the Nitroglycerin-Induced CamKIIalpha and CGRP Expression Changes. Headache [Epub ahead of print]. van den Maagdenberg AM, Pietrobon D, Pizzorusso T et al. (2004). A CACNA1A knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41: 701–710. Villalo´n CM, Centurio´n D, Valdivia LF et al. (2002). An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Proc West Pharmacol Soc 45: 199–210. Waeber C, Moskowitz MA (2005). Migraine as an inflammatory disorder. Neurology 64: S9–S15. Willems EW, Trion M, De Vries P et al. (1999). Pharmacological evidence that alpha1- and alpha2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Br J Pharmacol 127: 1263–1271. Willems EW, Valdivia LF, Villalo´n CM et al. (2003). Possible role of alpha-adrenoceptor subtypes in acute migraine therapy. Cephalalgia 23: 245–257.

123

Williamson DJ, Hargreaves RJ, Hill RG et al. (1997a). Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat – intravital microscope studies. Cephalalgia 17: 525–531. Williamson DJ, Hargreaves RJ, Hill RG et al. (1997b). Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia 17: 518–524. Williams S, Evan GI, Hunt SP (1990). Changing patterns of c-fos induction in spinal neurons following thermal cutaneous stimulation in the rat. Neuroscience 36: 73–81. Wolff HG (1972). Headache and Other Head Pain. Oxford University Press, New York. Wu D, Doods H, Arndt K et al. (2002). Development and potential of non-peptide antagonists for calcitoningene-related peptide (CGRP) receptors: evidence for CGRP receptor heterogeneity. Biochem Soc Trans 30: 468–473. Yamamura H, Malick A, Chamberlin NL et al. (1998). Cardiovascular and neuronal response to head stimulation reflect central sensitisation and cutaneous allodynia in a rat model of migraine. J Neurophysiol 81: 479–493.