Neuroscience 161 (2009) 327341

NEUROSCIENCE FOREFRONT REVIEW NEUROBIOLOGY OF MIGRAINE

P. J. GOADSBY,* A. R. CHARBIT, A. P. ANDREOU, S. AKERMAN AND P. R. HOLLAND
Headache Group, Department of Neurology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0114, USA

AbstractMigraine is a complex disorder of the brain whose mechanisms are only now being unraveled. It is common, disabling and economically costly. The pain suggests an important role of the nociceptive activation, or the perception of activation, of trigeminal cranial, particularly intracranial afferents. Moreover, the involvement of a multi-sensory disturbance that includes light, sound and smells, as well as nausea, suggests the problem may involve central modulation of afferent traffic more broadly. Brain imaging studies in migraine point to the importance of sub-cortical structures in the underlying pathophysiology of the disorder. Migraine may thus be considered an inherited dysfunction of sensory modulatory networks with the dominant disturbance affecting abnormal processing of essentially normal neural traffic. 2009 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: migraine, trigeminal, brainstem, orexin, dopamine, glutamate. Contents Trigeminovascular anatomy: structures that produce, or are perceived to produce, pain 327 What is the source of the pain? 328 Trigeminovascular physiology: peripheral connections: plasma protein extravasation (PPE) and CGRP 328 PPE 328 Neuropeptide studies 329 CGRP alone does not mediate PPE 329 Trigeminovascular physiology: the trigeminocervical complex (TCC) and beyond 329 The TCC 329 Therapeutic implications from the trigeminocervical complex: pharmacology 329 5-HT1F receptors 330 Orexin 330 Glutamate receptors 331 Cannabinoid receptors 331 Therapeutic implications from the trigeminocervical complex: neurostimulation 331 Higher order processing: thalamus and rostral 331 Thalamus 331
*Corresponding author. E-mail address: peter.goadsby@ucsf.edu (P. J. Goadsby). Abbreviations: CGRP, calcitonin gene-related peptide; CSD, cortical spreading depression; LC, locus coeruleus; NMDA, N-methyl-Daspar-tate; NRM, nucleus raphe magnus; ONS, occipital nerve stimulation; PAG, periaqueductal grey; PPE, plasma protein extravasation; TCC, trigeminocervical complex; TTH, tension-type headache; VIP, vasoac-tive intestinal polypeptide.

Cortical processing Central modulation of trigeminal pain PAG and the modulation of trigeminocervical nociceptive inputs Hypothalamic structures and the trigeminocervical complex Orexinergic neurons Dopaminergic influences on the trigeminocervical complex Conclusion References

332 333 334 334 334 334 334 335

Migraine is a complex disorder of the brain whose mechanisms are only now being unraveled (Lance and Goadsby, 2005). It is common ( Lipton et al., 2001), disabling ( Menken et al., 2000) and economically costly ( Stewart et al., 2003). It is stunning, and one might be so bold as to say irresponsible, how little resource has been directed at the problem ( Shapiro and Goadsby, 2007). Here we will review some areas of activity that show promise in terms of understanding migraine and areas where new approaches to management may be possible. Migraine is, of course, only one of the primary headache disorders ( Headache Classification Committee of the International Headache Society, 2004), and horrible problems like the trigeminal autonomic cephalalgias ( Goadsby et al., 2008; Goadsby and Lipton, 1997), such as cluster headache ( Goadsby, 2002b; Goadsby et al., 2007), are also being studied with basic anatomical principles applying to all these disorders. In this review we cover the basic neuroanatomy of migraine, transmitter pathways of relevance to the disorder and brain areas that seem relevant to the condition. The basic thesis being advanced is migraine is a disorder of altered perception of normality, e.g. normal light is perceived as painful, so that characterizing the neurobiology of intracranial nociceptive pathways and their regulation will, piece by piece, build a basis for understanding the disorder and thus for better treatments. Readers interested in a focus on details of the animal models ( Bergerot et al., 2006) or a more general clinical discussion ( Lance and Goadsby, 2005) are referred elsewhere. The genetics of migraine, particularly in reference to the rare form, familial hemiplegic migraine, has been addressed elsewhere ( Barrett et al., 2008; Ferrari and Goadsby, 2007).

TRIGEMINOVASCULAR ANATOMY: STRUCTURES THAT PRODUCE, OR ARE PERCEIVED TO PRODUCE, PAIN

Surrounding the large cerebral vessels, pial vessels, large venous sinuses and dura mater is a plexus of largely

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unmyelinated fibers that arise from the ophthalmic division of the trigeminal ganglion ( McNaughton, 1966) and in the posterior fossa from the upper cervical dorsal roots ( Arbab et al., 1986). Trigeminal fibers innervating cerebral vessels arise from neurons in the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP) ( Uddman et al., 1985). Stimulation of the cranial vessels, such as the superior sagittal sinus (SSS), is certainly pain-ful in humans ( Feindel et al., 1960; McNaughton and Fein- del, 1977), and dural nerves innervating the cranial vessels of humans largely consist of small diameter myelinated and unmyelinated fibers ( Cushing, 1904). Because perivascular dural stimulation is painful, and the pain is referred to the head ( Wolff, 1948), it is a good model for the pathways potentially involved in migraine.

make the strategies safer ( Dodick et al., 2004), a simple and completely desirable goal.

TRIGEMINOVASCULAR PHYSIOLOGY: PERIPHERAL CONNECTIONS: PLASMA PROTEIN EXTRAVASATION (PPE) AND CGRP
There is considerable experimental animal and human work to understand the physiology of the activation of trigeminal nociceptive afferents. These data allow us to build up a picture of what may happen during migraine and some plausible explanation of how the current acute anti-migraine compounds may work ( Table 1, Goadsby, 2000).

PPE
Moskowitz and colleagues (1990) have provided a series of experiments to suggest that some component of the pain of migraine may be a form of sterile neurogenic in-flammation. Neurogenic plasma extravasation can be seen during electrical stimulation of the trigeminal ganglion in the rat ( Markowitz et al., 1987), along with structural changes in the dura mater including mast cell degranula-tion ( Dimitriadou et al., 1991) and changes in post-capillary venules including platelet aggregation ( Dimitriadou et al., 1992). It has been shown that although plasma extravasa-tion in the retina, which is blockable by sumatriptan, could be seen after trigeminal ganglion stimulation in the rat, no changes are seen with retinal angiography during acute attacks of migraine or cluster headache ( May et al., 1998). A limitation of this study was the probable sampling of both retina and choroid elements in rat, given that choroidal vessels have fenestrated capillaries ( Steuer et al., 2004). Clearly blockade of neurogenic PPE is not completely predictive of antimigraine efficacy in humans as evi-denced by the failure in clinical trials of substance P, neurokinin-1 antagonists ( Connor et al., 1998; Diener and the RPR100893 Study Group, 2003; Goldstein et al., 1997; Norman et al., 1998), specific PPE blockers, CP122,288 ( Roon et al., 1997) and 4991w93 ( Earl et al., 1999), an endothelin antagonist ( May et al., 1996) and a neuroste-roid ganaxolone ( Data et al., 1998). Indeed substance P (neurokinin 1) receptor blockers also have no role in the

What is the source of the pain?

The pain process is likely to be a combination of direct factors, i.e. activation of the nociceptors of pain-producing intracranial structures, in concert with a reduction in the normal functioning of the endogenous pain control path-ways that normally gate that pain ( Goadsby et al., 1991). Certainly if the carotid artery is occluded ipsilateral to the side of headache in migraineurs then two-thirds will expe-rience relief ( Drummond and Lance, 1983), and distension of major cerebral vessels by balloon dilatation leads to pain referred to the ophthalmic division of the trigeminal nerve ( Martins et al., 1993; Nichols et al., 1993, 1990). However, the changes in diameter as measured are nothing like those achievable with balloon dilation ( Friberg et al., 1991; Limmroth et al., 1996). One position that is consistent with the data is that the dilation, when it is seen, is an epiphe-nomenon to the activation of the trigeminal-autonomic re-flex ( May and Goadsby, 1999). Since we accept photopho-bia and phonophobia are present without any hint that there is peripheral change, why should a peripheral change be important for the pain? The question is not trivial since, if correct, one would direct all efforts to neu-rally-based, specifically CNS-based, therapeutic develop-ment. There is a considerable unmet need to develop non-vascular antimigraine treatments because this would
Table 1. Neuroanatomical processing of vascular head pain Structure Structures innervated by the TCC Cranial vessels Dura mater 1st 2nd 3rd Final

Comments

Innervated by the ophthalmic branch of trigeminal nerve Trigeminal ganglion TCC (quintothalamic tract) Thalamus Cortex Middle cranial fossa Trigeminal n. caudalis and C1/C2 dorsal horns Ventrobasal complex Medial n. of posterior group intralaminar complex Insulae Frontal cortex Anterior cingulate cortex Basal ganglia Orexin-containing neurons

Modulatory

Hypothalamic Midbrain PAG Pons-LC

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preventive management of migraine ( Goldstein et al., 2001a). The role of dural neurogenic plasma extravasation has been recently reviewed ( Peroutka, 2005), and it is hard to sustain a pivotal role for it in migraine. The subject will be revisited somewhat below when discussing neuropep-tide studies supporting the notion that plasma extravasa-tion is simply not important in migraine biology.

an orally active CGRP receptor antagonist ( Williams et al., 2006), in migraine ( Ho et al., 2008, 2009). CGRP alone does not mediate PPE
There is no direct evidence that CGRP alone will produce increased vascular permeability in the dura mater ( Brain and Grant, 2004). In a study in the mouse CGRP was not active in the plasma extravasation assay ( Tam and Brain, 2004), but was a potent vasodilator ( Grant et al., 2004). Consistent with this, and in contrast to the mice who have a neurokinin-1 receptor knockout ( Kandere-Grzybowska et al., 2003), animals in which the -CGRP gene is disrupted still have a plasma extravasation response to application of mustard oil to the ear, which in turn can be blocked by a neurokinin-1 receptor antagonist ( Grant et al., 2005). Taken together it seems clear in the experimental setting that CGRP does not alone promote plasma extravasation, and that the efficacy of CGRP receptor antagonists in migraine does not provide any evidence for a role for PPE in the disorder.

NEUROPEPTIDE STUDIES
Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow ( Goadsby and Duckworth, 1987; Tran-Dinh et al., 1992) and local cranial release of both CGRP and substance P ( Goadsby et al., 1988). In the cat stimulation of the more nociceptive specific structure, the superior sag-ittal sinus, whose stimulation produces pain in humans ( Feindel et al., 1960), increases cerebral blood flow to a greater extent than trigeminal ganglion stimulation ( Goadsby et al., 1997). A substantial component of the trigeminovascular activation is mediated by a pathway tra-versing the superior salivatory nucleus ( Knight and Goadsby, 2000) and projecting through the greater super-ficial petrosal branch of the facial nerve ( Lambert et al., 1984), again releasing a powerful vasodilator peptide, va-soactive intestinal polypeptide (VIP) ( Goadsby and Mac- donald, 1985). Interestingly, the VIP-ergic innervation of the cerebral vessels is predominantly anterior rather than posterior ( Matsuyama et al., 1983). This may contribute to this regions vulnerability to spreading depression and in part explain why the aura is so very often seen to com-mence posteriorly. Stimulation of the superior sagittal si-nus increases cerebral blood flow and jugular vein CGRP levels ( Zagami et al., 1990). In humans CGRP is elevated in the headache phase of migraine when it is severe ( Gallai et al., 1995; Goadsby et al., 1990), cluster headache ( Fan- ciullacci et al., 1995; Goadsby and Edvinsson, 1994), chronic paroxysmal hemicrania ( Goadsby and Edvinsson, 1996) and in throbbing exacerbations of chronic tension-type headache (TTH, Ashina et al., 2000); the latter prob-ably migraine sufferers mislabeled as TTH. An exception is what seems to be less well-developed migraine in which CGRP is not elevated ( Tvedskov et al., 2005). In the round these data support the view that the trigeminovascular system may be activated in a protective role in these conditions. It is of interest in this regard that compounds which have not shown activity in human migraine, notably the conformationally restricted analogue of sumatriptan, CP122,288 ( Knight et al., 1999b), and the conformationally restricted analogue of zolmitriptan, 4991w93 ( Knight et al., 1999a), were both ineffective inhibitors of CGRP release after superior sagittal sinus stimulation in the cat. A clear answer for the importance of CGRP comes from studies of the potent, specific CGRP antagonist BIBN4096 ( Doods et al., 2000). This compound has no vascular actions ( Pe- tersen et al., 2004, 2005) and has been shown to be effective in the treatment of acute migraine ( Olesen et al., 2004). These data are further supported by the placebo-controlled trials that demonstrate the efficacy of MK-974,

TRIGEMINOVASCULAR PHYSIOLOGY: THE TRIGEMINOCERVICAL COMPLEX (TCC) AND BEYOND

The TCC
After stimulation of the superior sagittal sinus Fos-like immunoreactivity is seen in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in the cat ( Kaube et al., 1993c) and monkey ( Goadsby and Hoskin, 1997). Fos-like immunoreactivity can be observed bilater-ally after unilateral stimulation of the peri-dural tissue around the meningeal artery ( Hoskin et al., 1999). Activa-tion in the high cervical cord is consistent with similar data using 2deoxyglucose measurements with superior sagittal sinus stimulation ( Goadsby and Zagami, 1991) and consis-tent with the observations of Kerr ( Kerr, 1961; Kerr and Olafson, 1961), and recent human studies ( Piovesan et al., 2001). Direct evidence for activation of neurons in the high cervical cord from stimulation of both forebrain dura mater and regions innervated by the greater occipital nerve has been provided ( Bartsch and Goadsby, 2001, 2002). Taken together these data suggest a view of the trigeminal nucleus extending beyond the traditional nucleus caudalis boundary to the dorsal horn of the high cervical region in a functional continuum that includes a cervical extension. The entire group of cells could be regarded functionally as the TCC, and probably accounts for the largest part of the phenotype of the pain of primary headaches ( Bartsch and Goadsby, 2005).

Therapeutic implications from the trigeminocervical complex: pharmacology

If the trigeminocervical complex is the key structure providing cranial trigeminovascular nociceptive inputs, then its pharmacology may provide insights into acute and preventive medicine opportunities. Experimental pharmacological evidence suggests that some abortive anti-migraine drugs, such as, dihydroergotamine ( Hoskin et al., 1996), acetylsalicylic acid ( Kaube et al., 1993b), sumatriptan ( Kaube et al., 1993a),

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eletriptan ( Goadsby and Hoskin, 1999), naratriptan ( Cumberbatch et al., 1998; Goadsby and Knight, 1997), rizatriptan ( Cumberbatch et al., 1997), zolmitriptan ( Goadsby and Hoskin, 1996) and the clinically effective CGRP receptor antagonist BIBN-4096BS ( Storer et al., 2004), can have ac-tions at these second order neurons. Remarkably, and of importance for the general principle, this is also true for as-pirin ( Kaube et al., 1993b) and NSAIDs ( Jakubowski et al., 2007). Such an effect would reduce neuronal activity, provid-ing a clear site for therapeutic intervention in migraine. Some recently studied targets include the 5-HT1F receptor, orexin receptors, glutamate receptors and cannabinoid receptors and other targets in more advanced clinical trials are dis-cussed elsewhere ( Goadsby, 2005).

5-HT1F receptors
Activation of 5-HT1F receptors does not seem to have vascular effects ( Cohen and Schenck, 1999; Razzaque et al., 1999). LY334,370 is effective in acute migraine, albeit at doses with some CNS side effects and no cardiovascu-lar problems ( Goldstein et al., 2001b). Unfortunately its development was stopped because of a non-human toxic-ity problem not related to the mechanism but to the com-pound itself. 5-HT1F receptors are found in the trigeminal nucleus ( Castro et al., 1997; Fugelli et al., 1997; Pascual et al., 1996; Waeber and Moskowitz, 1995) and trigeminal ganglion ( Bouchelet et al., 1996). 5-HT1F receptor activa-tion is inhibitory in the trigeminal nucleus in rat ( Mitsikostas et al., 1999a) and cat, albeit in cat seeming less potent than 5HT1B or 5-HT1D receptor activation ( Goadsby and Classey, 2003). Using electron microscopic methods pre-synaptic 5HT1F receptors in the trigeminal nucleus of the cat have been reported ( Maneesri et al., 2004). It is clear there is a good expectation that 5-HT1F receptor agonists would be both anti-migraine and non-vascular. Initial re-sults with the 5HT1F agonist COL-144 demonstrate proof-of-concept in a placebo-controlled trial ( Reuter et al., 2009), offering a further promising advance in manage-ment derived from good bench science.

et al., 2001; Grudt et al., 2002; Yamamoto et al., 2002). To evaluate the potential for orexin receptor modulation of trigeminovascular nociceptive afferents the effects of i.v. orexin A and B on responses of neurons in the trigeminocervical complex were examined ( Holland et al., 2006). Orexin A inhibited the A-fiber responses to dural electrical stimulation, an effect reversed by pre-treatment with the OX1R antagonist SB-334867 ( Smart et al., 2001), which had no effect when given alone. Orexin B administration had no significant effect on trigeminal neuronal firing. These data suggest orexin A is able to inhibit A-fiber responses to dural electrical stimulation via activation of the OX1R. The data are consistent with a similar effect of inhibiting trigeminovascular activation in the dural circula-tion, again from local dural stimulation ( Holland et al., 2005a). Given that neurons in the hypothalamic area that is the source of CNS orexins can be activated with superior sagittal sinus stimulation ( Benjamin et al., 2004) and fur-ther that these neurons contain orexin ( Holland et al., 2005b), CNS orexin mechanisms are an interesting target for further study ( Fig. 1).
Fig. 1. Major orexinergic projections with importance to the modulation of trigeminovascular nociceptive processing. The hypothalamic orexinergic system (red arrows) projects to multiple systems involved in the modulation of nociceptive processing (blue arrows) at the level of the TCC. Orexin A inhibits trigeminovascular activation at the level of the dural vasculature when administered intravenously and in the TCC when administered intravenously or microinjected into the posterior hypothalamus. Orexin B has no known effect on trigeminovascular activation when administered intravenously, but demonstrates a facilitatory role when microinjected directly into the posterior hypothal-amus. Further possible mechanisms include a direct action on the PAG and LC. TG, trigeminal ganglion; CG, cervical ganglion. For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.

Orexin
Orexin A [hypocretin] and orexin B are two novel relatively recently described peptides selectively synthesized in the lateral and posterior hypothalamus ( Date et al., 1999; de Lecea et al., 1998; Marcus et al., 2001; Nambu et al., 1999; Peyron et al., 1998; Sakurai et al., 1998; Trivedi et al., 1998). Orexin A and B are proteolytically derived from the same prepro-orexin precursor protein ( Smart and Jerman, 2002) and bind to Gq-protein-coupled receptors named orexin 1 and 2 that act via PKC to phosphorylate voltageactivated calcium channels ( Van den Pol et al., 1998). Orexins have been implicated mainly in metabolic control and sleep ( Smart and Jerman, 2002), and have a pathophysiological role in narcolepsy ( Siegel, 1999). A role for the orexins in nociceptive processing has been postulated as application of orexin A elicits analgesic effects in be-havioral pain assays, although the exact mechanisms by which this pain-modulating effect is mediated and the com-plete role of the orexins are yet to be determined ( Bingham

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Glutamate receptors
Glutamate acts through both ionotropic (ion channel type) and G-protein-coupled (metabotrophic) receptor families. Glutamate-like immunoreactivity has been seen in tooth pulp neurons that project to the trigeminal nucleus caudalis in the rat ( Clements et al., 1991), while glutaminase immunoreactivity is most dense in the nucleus caudalis when compared with other parts of the trigeminal nucleus of the rat ( Magnusson et al., 1986). Each of N-methyl-D-aspar-tate (NMDA), AMPA, kainate and metabotropic glutamate receptors have been identified in the superficial laminae of the trigeminal nucleus caudalis of the rat ( Tallaksen- Greene et al., 1992). Ionotropic receptor channel blockers, such as MK-801 acting at the NMDA receptor, and GYKI-52466, acting at the AMPA receptor, have been found to block trigeminovascular nociceptive transmission in the trigeminocervical nucleus ( Classey et al., 2001; Goadsby and Classey, 2000; Storer and Goadsby, 1999). Similarly, both NMDA and non-NMDA ionotropic receptor blockade reduces Fos protein expression in trigeminal nucleus caudalis associated with intracisternal capsaicin injection ( Mitsikostas et al., 1998, 1999b), while strictly cervical afferent activation into the trigeminocervical complex also produces fos protein expression in the entire extent of the structure and is again reduced by MK-801 ( Le Doare et al., 2006). Evidence also exists for the plausible involvement of group III metabotropic glutamate receptors, as their modulation decreases fos expression in trigeminal nucleus caudalis in animal models of trigeminovascular nociceptive activation ( Mitsikostas et al., 1999b). Moreover, it seems clear that the kainate receptor, particularly iGluR5 kainate subunit, activation is certainly important for both trigemi-nocervical transmission after activation of durovascular afferents ( Andreou et al., 2007) and local dural vessel changes with dural afferent stimulation ( Andreou et al., 2009). The important clinical correlates here are the pos-itive results with the AMPA/kainate receptor antagonist LY293558 ( Sang et al., 2004) and the further positive results with LY466195 ( Johnson et al., 2008), a specific iGluR5 kainate receptor blocker ( Weiss et al., 2006). More-over, some part if the pharmacology of topiramate includes modulation of kainateevoked neural responses ( Rosen- feld, 1997), further supporting this target for migraine ther-apeutics ( Fig. 2).

induced and nitric oxide (NO)induced dural vessel dilation ( Fig. 3) ( Akerman et al., 2004b). Moreover, anandamideinduced dural dilation was blocked by the TRPV1 receptor antagonist capsazepine ( Akerman et al., 2004a). Anandamide is structurally related to capsaicin and olvanil ( Nvanillyl-9-oleamide) and both are TRPV1 agonists, which are known to have effects in the durovascular model albeit not as prominent as other systems we have studied ( Ak- erman et al., 2003). From these data one might predict that TRPV1 approaches to acute migraine in clinic, currently being tested in clinical trials, will fail, while CB receptor approaches have more promise ( Akerman et al., 2007).

Therapeutic implications from the trigeminocervical complex: neurostimulation

Weiner and Read (1999) reported a series of cases of intractable occipital neuralgia responding to occipital nerve stimulation (ONS). Detailed phenotyping of these cases in association with a functional imaging study demonstrated that almost all had chronic migraine. Experience with ONS in the chronic migraine patients of Weiner and Read (1999) suggested that it may be helpful therapeutically ( Matharu et al., 2004). Indeed using positron emission tomography (PET) it could be shown that thalamic changes appeared to determine the outcome of therapy and randomized dou-bleblinded placebo-controlled trials are now ongoing in chronic migraine ( Goadsby et al., 2005), while open label experience has been reported in the TACs ( Goadsby and Lipton, 1997) consist of cluster headache, paroxysmal hemicrania and SUNCT/SUNA (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features, Headache Classification Committee of the International Headache Society, 2004). This initial experience ( Burns et al., 2007a; Magis et al., 2007) has been very similar and certainly encouraging. Six of eight of our patients had sufficient benefit to both recommend the procedure to others and not wish to be considered for other neurostimulation approaches, specifically deep brain stimulation ( Leone, 2006). Our long term experience over more than 2 years demonstrates that device dysfunction almost always leads to the return of attacks ( Burns et al., 2007b). This is an exciting new development that directly comes from the basic science laboratory characterization of trigeminocervical anatomy and physiology and is now in clinical trial ( Goadsby, 2007).

Cannabinoid receptors
Arachidonylethanolamide (AEA or anandamide) is be-lieved to be one of the endogenous ligands to the canna-binoid CB1 and CB2 receptors ( Devane et al., 1992; Hoehe et al., 1991; Matsuda et al., 1990; Munro et al., 1993). The known 9 behavioral effects of anandamide are similar to that of tetrahydrocannabinol, the psychoactive constituent of cannabis, being anti-nociception, catalepsy, hypother-mia and depression of motor activity ( Adams et al., 1998; Crawley et al., 1993; Dewey, 1986; Smith et al., 1994). Using the model of intravital microscopy ( Williamson et al., 1997), it has been shown that blocking the CB1 receptor attenuated each of neurogenic dural vasodilation, CGRP-

HIGHER ORDER PROCESSING: THALAMUS AND ROSTRAL

Thalamus
Following transmission in the caudal brain stem and high cervical spinal cord information is relayed in a group of fibers (the quintothalamic tract) to the thalamus. Processing of vas-cular pain in the thalamus occurs in the ventroposteromedial thalamus, medial nucleus of the posterior complex and in the intralaminar thalamus ( Zagami and Goadsby, 1991). ( Zagami and Lambert, 1991) has shown by application of capsaicin to the superior sagittal sinus that trigeminal projections with a high degree of nociceptive input are processed in neurons

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Fig. 2. Kainate receptors and the trigeminovascular system. Kainate receptors (iGluR5-7, KA1, KA2 subunits) are expressed in key structures of the nociceptive pathway, including the trigeminal ganglion (TG), TCC, ventrobasal thalamus and cingulate cortex. In vitro experiments have demonstrated that kainate receptors function as modulators of synaptic transmission and plasticity by regulating post-synaptic currents and presynaptic neuro-transmitters release. The presence of iGluR5 subunits in the TG indicates their presynaptic localization on primary afferent s in the TCC, as well as their prejunctional localization on fibers surrounding dural vessels. In the spinal cord, kainate receptors are also located postsynaptically on second order neurons and presynaptically on GABAergic interneurons. Although the subunit composition of kainate receptors in the thalamus remains unidentified, presynaptic iGluR5 receptors on interneurons modulate inhibitory neurotransmission. The thalamus relays information to the somato-sensory cortex and cingular cortex, where iGluR5 and iGluR6 kainate receptors are present and presynaptic iGluR5 receptors on interneurons modulate GABA release. (A, B) Microiontophoretic ejection of iGluR5 antagonist in the TCC caused a differential response with both inhibition and facilitation in different subpopulations of neurons, activated in response to dural vessel electrical stimulation, by acting at either postsynaptic or presynaptic sites. (C) I.v. administration of iGluR5 agonist inhibited neurogenic dural vasodilation.

particularly in the ventroposteromedial thalamus and in its ventral periphery. These neurons may be a target for preventive treatments; certainly they are inhibited by -adrenoceptor blockers, such as propranolol ( Shields and Goadsby, 2005). Remarkably they may also be a target for other approaches including 5-HT1B/1D receptor agonists, since microiontophoresis of naratriptan on ventroposteromedial thalamic neurons inhibits their activation by trigeminal nociceptive afferent stimulation ( Shields and Goadsby, 2006), as does iGluR5kainate glutamate receptor antagonists ( Andreou and Goadsby, 2008). Human imaging studies have confirmed activation of thalamus contralateral to pain in acute migraine ( Afridi et al., 2005a; Bahra et al., 2001).

Cortical processing
Pain in general is a complex phenomenon that is mediated by a network of neuronal structures, including cingulate cortex, insulae and thalamus ( Derbyshire et al., 1997; Jones et al., 1991a; Melzack and Casey, 1968). One framework proposes medial (thalamus, anterior cingulate cortex and prefrontal cortex) and lateral (primary and secondary somatosensory cortex) pain systems and these have been investigated using functional imaging tech-niques ( Jones et al., 1991b). Most functional imaging stud-ies demonstrate activation in these structures with clinical or experimental pain and recent reviews are available ( Apkarian and Chialvo, 2006; Chen, 1993; Derbyshire et al., 1997; Peyron et al., 2000). Recently, the amygdala ( Bernard et al., 1992; Derbyshire et al., 1997; Hsieh et al., 1996), basal ganglia ( Chudler and Dong, 1995; Derbyshire et al., 1997) and posterior parietal cortex ( Dong et al., 1996) have also been implicated in CNS responses to pain. It has been shown in migraine that anterior cingulate cortex, frontal cortex and visual and auditory association

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Fig. 3. Cannabinoids and the trigeminovascular system. Overview of the major cannabinoid projections (green lines) thought to be involved in modulation of trigeminovascular neuronal firing, and the other major (black lines) interactions thought to modulate the trigeminovascular system. I.v. administration of cannabinoid CB1 receptor agonists in-hibits dural vessel dilation and neuronal firing in the TCC, implying that CB 1 receptors are present on trigeminovascular neuronal projections. Cannabinoids are thought to inhibit the release of glutamate from primary afferents present in laminae I and II, and also indirectly via interneurons ( Farquhar-Smith et al., 2000; Jennings et al., 2001; Morisset et al., 2001). It is also known that CB1 receptors are present in the PAG, primarily on the terminals of GABAergic neurons ( Maione et al., 2006; Tsou et al., 1998) and microinjection of CB1 receptor agonists is anti-nociceptive in thermal plantar, tail-flick and formalin tests ( de Novellis et al., 2005; Finn et al., 2003; Palazzo et al., 2001). Descending projections from the ventrolateral PAG are known to modulate neurons of the TCC, we therefore also highlight a descend-ing cannabinoid (green line) projection from the PAG to TCC where we believe cannabinoid microinjection into the PAG can modulate TCC firing. TG, trigeminal ganglion; CG, cervical ganglion. For interpreta-tion of the references to color in this figure legend, the reader is referred to the Web version of this article.

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cortex are activated during acute attacks ( Bahra et al., 2001; Weiller et al., 1995). Certainly there are cortical blood flow changes with migraine aura ( Cutrer et al., 1998; Hadjikhani et al., 2001; Sanchez del Rio et al., 1999). The aura is believed to be a wave of cortical spreading depression (CSD) which spreads out from the occipital lobe across the cortex ( Olesen, 1991). Bolay and colleagues (2002) have shown that CSD in rats increases neural activity in the ipsilateral trigeminal nucleus, although con-tradictory preclinical data also exist ( Ebersberger et al., 2001; Lambert et al., 1999). Recently, it has been suggested that

cortex activation can indirectly through activa-tion of the nucleus raphe magnus (NRM) to alter pain responses ( Lambert et al., 2008b). How these areas relate to one another and the processing is unknown and will require challenging and technically difficult experiments to untangle. A recent functional imaging study suggests that cortical regions, particularly the orbito-frontal cortex, may be important in medication overuse headache ( Fumal et al., 2006). This problem is both widespread and in need of study in some detail.

the attack? It has been shown in the experimental animal that stimulation of a discrete nucleus in the brain stem, nucleus locus coeruleus (LC) (the main central noradrenergic nucleus) reduces cerebral blood flow in a frequency-depen-dent manner ( Goadsby et al., 1982) through an 2-adre-noceptorlinked mechanism ( Goadsby et al., 1985). This reduction is maximal in the occipital cortex ( Goadsby and Duckworth, 1989). While a 25% overall reduction in cere-bral blood flow is seen, extracerebral vasodilatation occurs in parallel ( Goadsby et al., 1982). In addition the main 5-HT-containing nucleus in the brain stem, the midbrain dorsal raphe nucleus, can increase cerebral blood flow when activated ( Goadsby et al., 1991). The NRM and the adjacent reticular formation are known to modulate sen-sory responses of neurons in the spinal trigeminal nucleus ( Sessle et al., 1981), sending serotonergic projections to both the trigeminal nucleus oralis and caudalis and to the spinal cord in the cat and rat ( Lovick and Robinson, 1983; Lovick and Wolstencroft, 1983). Stimulation of the NRM produced potent inhibition of TCC nociceptive and non-nociceptive neuronal responses ( Chiang et al., 1994; Lam- bert et al., 2008b). NRM has also been shown to be modulated by cortical mechanisms, as the inhibitory ef-fects of this nucleus on trigeminal neurons can be antag-onized by multiple waves of CSD, further suggesting an indirect modulation of the TCC by cortical activation via the cortico-NRM-trigeminal neuraxis ( Lambert et al., 2008a,b). Following stimulation of the superior sagittal sinus Fos expression is increased in the ventrolateral periaqueductal

CENTRAL MODULATION OF TRIGEMINAL PAIN

A key observation, perhaps the crucial observation of functional imaging in migraine, has been that brainstem areas are active during pain and that after successful treatment this activation persists ( Afridi et al., 2005a,b; Bahra et al., 2001; Denuelle et al., 2004; Weiller et al., 1995). The areas active are in the dorsal midbrain and the dorsolateral pons, with most recently some suggestion of hypothalamic acti-vation ( Denuelle et al., 2007). The dorsal midbrain activa-tion corresponds with the brain region that Raskin (1987) initially reported, and Veloso et al. (1998) confirmed, to cause migraine-like headache when stimulated in patients with electrodes implanted for pain control. Moreover, le-sions from, for example multiple sclerosis ( Haas et al., 1993), or a developmental venous anomaly ( Goadsby, 2002a), also produce migraine. What are the roles for these areas in the disorder; are they in initiation, mainte-nance or termination of

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grey (PAG) matter in cat and monkey ( Hoskin et al., 2001). Similarly, stimulation of this region will inhibit sagittal sinus evoked trigeminal neuronal activity in cat ( Knight and Goadsby, 1999a). The ventrolateral PAG would certainly have been included within the area of activation on the human neuroimaging studies outlined above, so its physiology and interactions with the trigeminovascular system are of particular interest, as is the physiology of the dorsal pontine structure so reproducibly demonstrated on brain imaging.

LC neurons discussed in the brain imaging section above as pivotal participants in migraine pathophysiology. Dopaminergic influences on the trigeminocervical complex
The trigeminocervical complex conveys somatosensory and visceral nociceptive information from the head and orofacial structures to the hypothalamus ( Malick and Burstein, 1998; Malick et al., 2000). Additionally the hypothalamus contributes to the descending modulation of pain which projects to the spinal cord ( Fleetwood-Walker et al., 1988; Holden and Naleway, 2001; Workman and Lumb, 1997). More specifically dopamine exerts antinociceptive effects when microiontophoresed directly into neurons in the TCC activated by trigeminovascular nociceptive inputs ( Bergerot et al., 2007). Immunohistochemistry further dem-onstrates that both D1-like and D2-like dopamine receptors can be identified in the TCC ( Bergerot et al., 2007). One candidate for the origin of this dopaminergic modulation is the hypothalamic A11 dopaminergic nucleus first identified by Dahlstrom and Fuxe (1964) that is distributed along the rostro-caudal axis, in the periventricular posterior region of the hypothalamus and the periventricular gray of the cau-dal thalamus. The A11 nucleus is known to send direct inhibitory projections to the spinal cord dorsal horn ( Ondo et al., 2000; Ridet et al., 1992; Skagerberg et al., 1982; Takada et al., 1988; Tamae et al., 2005), and is also believed to be the sole source of dopamine in the spinal cord ( Holstege et al., 1996). Dopamine fibers and terminals are located throughout the spinal grey matter ( Holstege et al., 1996), as are dopamine receptors ( Levant and McCarson, 2001). Moreover, it has been shown that do-pamine and D2 receptor agonists inhibit transmission of nociceptors when applied directly to the spinal cord ( Barasi et al., 1987; Barasi and Duggal, 1985; FleetwoodWalker et al., 1988; Tamae et al., 2005). It can be shown that stimula-tion of the A11 nucleus inhibits nociceptive trigeminocervical afferents through a mechanism that can be attenuated by specific D2-like receptor antagonists ( Charbit et al., 2006). Furthermore, lesioning the area facilitates both nociceptive and non-nociceptive trigeminocervical afferent activity ( Char- bit et al., 2007), such that one might hypothesize that the A11 provides a tonic level of inhibition of nociceptive neuronal firing and dysfunction of A11 modulatory neurons would re-sult in a perception of pain in the head without necessarily any change in peripheral signaling ( Fig. 4). A further observation is that innocuous afferent activity, which is unaffected during stimulation of the A11, is signifi-cantly facilitated during lesioning of the nucleus. Could it be that a dysfunction in A11 descending inhibitory activity might be responsible for the allodynia that accompanies migraine?

PAG AND THE MODULATION OF TRIGEMINOCERVICAL NOCICEPTIVE INPUTS

Stimulation of nociceptive trigeminovascular afferents leads to fos protein expression in the ventrolateral PAG ( Hoskin et al., 2001). Activation of these neurons by direct electrical ( Knight and Goadsby, 2001) or chemical ( Knight et al., 2003) stimulation inhibits trigeminovascu-lar nociceptive traffic in the trigeminocervical complex. Remarkably, local injection of the P/Q voltage-gated calcium channel blocker agatoxin facilitates nociceptive trigeminovascular traffic ( Knight et al., 2002), and this very target is the recognized cause of familial hemiple-gic migraine in about 55% of cases ( Ophoff et al., 1996). Moreover, local injection of naratriptan, the 5-HT1B/1D receptor agonist that is a well-established treatment of acute migraine ( Goadsby et al., 2002), not only inhibits trigeminovascular nociceptive traffic in the trigeminocervical complex but also has no effect on nociceptive thermal facial stimuli ( Bartsch et al., 2004a). Taken together the data suggest a unique, important role for the ventrolateral PAG in migraine.

HYPOTHALAMIC STRUCTURES AND THE TRIGEMINOCERVICAL COMPLEX

Orexinergic neurons
Stimulation of nociceptive trigeminovascular afferents leads to activation of neurons in the posterior hypothala-mus ( Benjamin et al., 2004). Injection of orexin A (see above under pharmacological targets) into the posterior hypothalamus decreases the A- and C-fiber responses to dural electrical stimulation as well as spontaneous activity in trigeminal nucleus caudalis neurons ( Bartsch et al., 2004b). Responses to noxious thermal stimulation of the facial skin were also decreased by orexin A. Injection of orexin B into the posterior hypothalamus, however, elicited increased responses to dural stimulation in A- and C-fiber input neurons studied and resulted in increased spontane-ous activity. Responses to facial thermal stimulation were also increased by orexin B ( Bartsch et al., 2004b). These data suggest a differential modulation of dural nociceptive input by orexin 1 and 2 receptor activation in the posterior hypothalamus. In this light it is remarkable that orexin receptors influence pontine nucleus LC firing rates ( Hagan et al., 1999; Soffin et al., 2002), given the possible role of

CONCLUSION
Migraine is both complex from a biological viewpoint and important from both societal and patient perspectives. Its

understanding will not stem from one approach to its study or from work restricted to the bench or simply clinical observation. Migraine needs, demands and deserves attention from basic scientists, translational clinicians and

clinical practitioners so that its complex and fascinating neurobiology can be understood to make the world a better place for people with primary headache disorders.