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date: 08 April 2020

Neurobiological Basis of Migraine

Abstract and Keywords

Migraine is the most common disabling primary headache globally. Attacks often present with unilateral throbbing headache and an array of associated symptoms, including, nausea, multisensory hypersensitivity, and marked fatigue. The diverse symptomatology highlights the complexity of migraine as a whole nervous system disorder involving somatosensory, autonomic, endocrine, and arousal networks. While attempts to describe the entirety of migraine are complex and daunting, this chapter focuses on recent advances in the understanding of its pathophysiology and treatment. The chapter focuses on the underlying neuroanatomical basis for migraine-related headache and associated symptomatology and discusses key clinical and preclinical findings that indicate that migraine likely results from dysfunctional homeostatic mechanisms. Whereby abnormal central nervous system responses to extrinsic and intrinsic cues may lead to increased attack susceptibility. Finally, the chapter considers the recent translational success of targeted calcitonin gene-related peptide and serotonin 1F receptor (5-HT1F) modulation for migraine.

Keywords: migraine, headache, trigeminal, trigeminovascular system, homeostatic networks, pain, aura, cortical spreading depression, novel therapies

Migraine affects 8%–25% of the global population (Lipton et al., 2007; Lipton, Stewart, Diamond, Diamond, & Reed, 2001). Given the high prevalence, it is unsurprising that migraine alone contributes 5.6% of all years lost to disability, making it the leading cause of disability in those under 50 (Steiner, Stovner, Vos, Jensen, & Katsarava, 2018; Stovner et al., 2018) and the sixth most disabling of all disorders (Stovner et al., 2018). Attacks commonly present as bouts of moderate-to-severe unilateral throbbing headache lasting 4 to 72 hours (Headache Classification Committee, 2018); however, the head pain component of migraine represents only one single, albeit highly disabling, facet of the disorder (Goadsby, Holland, et al., 2017). Attacks commonly initiate with characteristic premonitory symptoms (marked fatigue, photophobia, difficulty concentrating, and neck stiffness) that are highly predictive of an ensuing headache (Giffin et al., 2003); may include aura symptoms (20%–30% of cases) (Headache Classification Committee, 2018); and are associated with nausea and multimodal sensory alterations, resulting in an aversion to touch (allodynia), light (photophobia), sound (phonophobia), and smell (osmophobia) (Goadsby, Holland, et al., 2017). In addition, there can be considerable cranial autonomic involvement, including lacrimation, reddening of the eye, and facial flushing present during migraine attacks (Gelfand, Reider, & Goadsby, 2013; Lai, Fuh, & Wang, 2009; Obermann et al., 2007); such features are characteristic, and more prominent, of the trigeminal autonomic cephalalgias, a group of related primary headache disorders (Headache Classification Committee, 2018).

Pathophysiology of Head Pain Pathways

In the pathophysiology of head pain pathways, the exact basis for initiation and cessation of attacks remains elusive.

Primary Afferent Input

While headache is one of the most salient features of migraine, the exact basis for the initiation and cessation of recurrent attacks remains elusive. Despite this enigma, the underlying head pain processing pathways are relatively well studied (Akerman, Holland, & Goadsby, 2011) and share several homologies with non–trigeminal-mediated pain processing. Trigeminal afferents arising in the trigeminal ganglion innervate almost all cranial tissues, including the intracranial and extracranial structures of the head and face (McNaughton & Feindel, 1977; Penfield & McNaughton, 1940; Ray & Wolff, 1940), with additional cervical afferents from the upper cervical dorsal root ganglion innervating the occipital regions (Figure 1). While cranial innervation exists from all three divisions of the trigeminal nerve, the ophthalmic division is considered the most relevant for migraine given the common distribution of head pain around the periorbital dermatome.

Neurobiological Basis of Migraine

Figure 1. Sensory afferents converging on the trigeminocervical complex. Primary afferents whose cell bodies lie in the trigeminal ganglion (TG) convey sensory information from the intracranial and extracranial structures of the head to the trigeminal nucleus caudalis (TNC) and the associated first and second cervical (C1, C2) levels that together form the trigeminocervical complex. The trigeminal sensory information arises from the mandibular (V3), maxillary (V2), and ophthalmic (V1) branches of the trigeminal nerve, with V1 of particular interest to migraine given the often-experienced periorbital pain. The trigeminocervical complex (TCC) also receives convergent sensory inputs from the posterior dura and cervical dermatomes that synapse in the second to fourth cervical levels and are considered to underlie migraine-relevant occipital head and neck pain.

These trigeminal afferents express calcitonin gene–related peptide (CGRP), substance P, neurokinin A, and pituitary adenylate cyclase–activating polypeptide (Figure 2) (Edvinsson, Brodin, Jansen, & Uddman, 1988; Uddman & Edvinsson, 1989; Uddman, Edvinsson, Ekman, Kingman, & McCulloch, 1985; Uddman, Goadsby, Jansen, & Edvinsson, 1993), the proportion of transmitter varying with target (O’Connor & van der Kooy, 1988). The afferents largely consist of thinly myelinated and unmyelinated Aδ and C fibers synapsing centrally on second-order trigeminothalamic relay neurons in the dorsal horn of the trigeminal nucleus caudalis and its cervical extensions (trigeminocervical complex) (Burstein, Yamamura, Malick, & Strassman, 1998; Holland, Akerman, & Goadsby, 2006; Liu, Broman, & Edvinsson, 2004, 2008; Millan, 2002).

Neurobiological Basis of Migraine

Figure 2. Perivascular innervation of intracranial vessels. Trigeminal sensory nerves arising in the trigeminal ganglion (TG) express calcitonin gene–related peptide (CGRP), substance P (SP), neurokinin A (NKA), and pituitary adenylate-cyclase–activating polypeptide (PACAP). Parasympathetic fibers arising in the sphenopalatine ganglia (SPG) and otic ganglia express PACAP, acetylcholine (AChE), vasoactive intestinal peptide (VIP), peptide histidine methionine (PHM), and nitric oxide synthase (NOS). Sympathetic nerves arising in the superior cervical ganglion (SCG) express noradrenaline (NA), neuropeptide Y (NPY), and adenosine triphosphate (ATP).

While the majority of the trigeminovascular afferents project to the trigeminocervical complex, recent studies have implicated potential additional projections that may help explain both the presence of autonomic features and the heightened perception of painful stimuli to the face. Direct projections from trigeminal ganglion afferents have been demonstrated to synapse in the ipsilateral parabrachial nucleus of mice (Rodriguez et al., 2017). This is in addition to the established indirect parabrachial innervation from the trigeminocervical complex (Cechetto, Standaert, & Saper, 1985; Dallel, Ricard, & Raboisson, 2004; Panneton & Gan, 2014; C. K. Zhang et al., 2018). This suggests that two alternate pathways arising from craniofacial nociceptors innervate the parabrachial nucleus and may in part explain the heightened perception of pain in the head and face, as compared to noncephalic pain. This trigeminoparabrachial-limbic pathway (Figure 3) is considered to process affective–motivational aspects of pain. Optogenetic inhibition of lateral parabrachial neurons reduced capsaicin-evoked facial allodynia, while their activation evoked aversive behaviors (Rodriguez et al., 2017). The importance of this convergent trigeminoparabrachial-limbic pathway remains to be fully elucidated; however, as discussed further in the chapter, migraine has been linked to dysfunctional bodily homeostatic mechanisms, whereby abnormal behavioral sensory responses are evoked in response to normal stimuli (e.g., touch and light). The parabrachial nucleus is a key hub in the maintenance of energy balance (Waterson & Horvath, 2015). CGRP-expressing neurons from the parabrachial nucleus project to the central nucleus of the amygdala, where they act to reduce appetite (Carter, Soden, Zweifel, & Palmiter, 2013) and modulate conditioned taste aversion (Carter, Han, & Palmiter, 2015). It has recently been demonstrated that this may include the convergence of trigeminal somatosensory and taste signals, specifically those parabrachial gustatory neurons responding to threatening stimuli, such as high salt concentration and bitter-tasting stimuli (J. Li & Lemon, 2019).

Neurobiological Basis of Migraine

Figure 3. The trigeminoparabrachial-limbic pathway. Primary sensory afferents arising in the trigeminal ganglion (TG) that innervate the ophthalmic (V1), maxillary (V2), and mandibular (V3) dermatomes synapse centrally on the trigeminocervical complex. Second-order neurons from the trigeminocervical complex (TCC) ascend to the brainstem parabrachial nucleus (PBN). Recently, a proposed direct TG-to-parabrachial pathway was proposed that bypasses the TCC and sends direct sensory information from the head and face to the PBN (Rodriguez et al., 2017). The PBN then sends projections to the amygdala (AM) that has projections to the insular cortex (IC) and cingulate cortex (CC). This convergent input of trigeminal sensory information on the PBN that is not observed from dorsal root ganglion afferents is proposed in part to explain the heightened perception of pain in the head and face.

In addition to this trigeminal parabrachial innervation, the presence of CGRP-immunoreactive fibers and CGRP receptors (Csati, Tajti, Tuka, Edvinsson, & Warfvinge, 2012) in the sphenopalatine ganglion (Ivanusic, Kwok, Ahn, & Jennings, 2011) that conveys parasympathetic outflow to the head and face (Figure 4) (Akerman et al., 2011) raises the possibility that trigeminovascular afferents expressing CGRP project directly from the trigeminal ganglion to the sphenopalatine ganglion (Csati et al., 2012). Alternatively, a direct trigeminocervical complex to superior salivatory nucleus pathway, which provides the primary parasympathetic projections to the sphenopalatine ganglion, forming a trigeminal autonomic reflex (May & Goadsby, 1999) has been postulated; however, a direct ascending trigeminocervical complex to sphenopalatine ganglion/superior salivatory nucleus projection remains to be demonstrated.

Neurobiological Basis of Migraine

Figure 4. The trigeminal autonomic reflex. Sensory afferents arising in trigeminal ganglion (TG) innervate all three divisions of the facial dermatome (V1–V3) and synapse centrally on the trigeminocervical complex (TCC). Activation of the trigeminal autonomic reflex between the TCC and superior salivatory nucleus (SuS) is proposed to result in increased parasympathetic outflow to the face via the sphenopalatine ganglion (SPG), resulting in ipsilateral cranial autonomic symptoms that include facial flushing, lacrimation, and rhinorrhea. The presence of CGRP-expressing fibers and CGRP receptors in the SPG has raised the potential that direct TG-to-SPG projections could also exist and impact this reflex pathway. To date, the direct connections shown in red dashed lines remain to be confirmed.

The modulation of the activity of this trigeminal autonomic reflex may underlie autonomic-mediated attack thresholds in patients. It receives direct reciprocal projections from hypothalamic, parabrachial, limbic, and cortical regions (Hosoya, Matsushita, & Sugiura, 1983; C. Y. Li et al., 2010; Noseda et al., 2017; Takeuchi, Fukui, Ichiyama, Miyoshi, & Nishimura, 1991) that play prominent roles in the regulation of appetite, energy balance, sleep–wake cycles, and stress responses, which could result in state-dependent susceptibility (e.g., based on circadian output from the suprachiasmatic nucleus). While preclinical studies in rats have demonstrated that activation of the trigeminal autonomic reflex via stimulation of the superior salivatory nucleus leads to increased neuronal responses in the trigeminocervical complex (Akerman, Holland, Lasalandra, & Goadsby, 2009; Akerman, Holland, Summ, Lasalandra, & Goadsby, 2012), the data do not conclude if transmission occurs directly between the superior salivatory nucleus and the trigeminocervical complex or if this may happen at a peripheral synapse that connects the trigeminal and parasympathetic pathways. Evidence from human studies, albeit in cluster headache, that activated the parasympathetic outflow to the face via direct stimulation of the sphenopalatine ganglion suggests that activation of the peripheral branch of the trigeminal autonomic reflex alone is insufficient to induce head pain (Guo et al., 2018), highlighting a potential key role for the central trigeminocervical complex to superior salivatory nucleus reflex, which may in combination lead to altered attack triggering thresholds.

Trigeminocervical Ascending Pathways

Sensory information from the trigeminocervical complex projects to several key nuclei throughout the brain (Figure 5) (Burstein, Cliffer, & Giesler, 1987, 1990; Liu et al., 2008; Liu, Broman, Zhang, & Edvinsson, 2009; Malick & Burstein, 1998; Malick, Jakubowski, Elmquist, Saper, & Burstein, 2001; Malick, Strassman, & Burstein, 2000; Matsushita, Ikeda, & Okado, 1982; Shigenaga et al., 1983; Veinante, Jacquin, & Deschenes, 2000; Williams, Zahm, & Jacquin, 1994), with dural nociceptive projections largely targeting the ventroposteromedial thalamic nuclei (Burstein et al., 1998, 2010; Zagami & Lambert, 1990, 1991), with spinal dorsal horn neurons largely targeting the ventroposterolateral nuclei. While the ventroposteromedial nuclei are considered the major target of trigeminothalamic projections, trigeminal inputs also synapse in the posterior and intralaminar thalamic nuclei. In addition, trigeminovascular sensory information is relayed to key medullary (rostral ventromedial medulla, nucleus raphe magnus, and parabrachial); brainstem (ventrolateral periaqueductal gray, nucleus of the solitary tract, and locus coeruleus); and diencephalic (lateral, anterior, and posterior hypothalamic nuclei) regions.

Neurobiological Basis of Migraine

Figure 5. Ascending projections from the trigeminocervical complex (TCC). In addition to the proposed parabrachial and trigeminal autonomic projections highlighted previously, second-order neurons from the TCC ascend to the thalamus, where trigeminal sensory information is then relayed to multiple cortical regions. Direct and indirect ascending projections also exist with several key nuclei, including the rostral ventromedial medulla (RVM), locus coeruleus (LC), periaqueductal gray (PAG), and hypothalamus.

The thalamus likely represents a key first stage for multimodal sensory integration (Tyll, Budinger, & Noesselt, 2011) in migraine, with important roles in nociceptive, touch, visual, olfactory, and auditory sensation. As such, the thalamus has emerged as a potential target for modulating the multimodal sensory dysfunction of migraine. This is supported by evidence demonstrating the convergence of retinal (light-sensitive) and trigeminovascular (dural nociceptive) projections in the posterior thalamus of rats, whereby light stimuli were observed to facilitate trigeminovascular nociceptive activation in thalamocortical relay neurons (Noseda et al., 2010), with important implications for the aversive nature of light in migraine (photophobia). Recently, a direct role for the ventroposteromedial nuclei in multimodal sensory integration has emerged. Detailed multielectrode recordings from the rat primary sensory/visual and ventroposteromedial nucleus/dorsal lateral geniculate nucleus simultaneously identified that bimodal (sensory and light) stimulation led to potentiation of sensory-evoked activity in the ventroposteromedial nucleus and increased coupling and signaling between the ventroposteromedial nucleus and primary sensory cortex (Bieler, Xu, Marquardt, & Hanganu-Opatz, 2018). This multimodal sensory integration was specific to the ventroposteromedial nucleus and did not occur in the dorsal lateral geniculate nucleus. Given that the ventroposteromedial nucleus is the primary interface for trigeminal-mediated signaling, it is possible that such multimodal sensory integration could further explain the aversive nature of light, sound, and smell in migraine (Schwedt, 2013). Further, the thalamus has been linked to the presence of extracephalic allodynia during migraine attacks, with both tactile and thermal stimuli enhancing pulvinar thalamic activity in migraine patients suffering from extracephalic allodynia (Burstein et al., 1998, 2010). In agreement, preclinical studies in rats have identified trigeminothalamic sensitization in response to meningeal inflammation in the ventroposteromedial nucleus and posterior and lateral posterior nuclei (Burstein et al., 2010).

Modulation of Trigeminovascular Processing

The head pain processing trigeminovascular system is subject to powerful modulation at several levels, largely originating from corticofugal projections to multiple brainstem regions, including the periaqueductal gray, pontine, raphe, and medullary reticular nuclei (Millan, 2002; Porreca, Ossipov, & Gebhart, 2002). Direct corticotrigeminocervical complex projections originating largely in the primary somatosensory, visual, and insular cortices have been shown to modulate trigeminocervical complex neuronal activity (Figure 6).

Neurobiological Basis of Migraine

Figure 6. Descending modulatory projections to the trigeminocervical complex (TCC). The TCC receives direct and indirect modulatory inputs arising in several cortical regions. Hypothalamic projections to the brainstem, which can be either direct or indirect via the periaqueductal gray (PAG) and locus coeruleus (LC), may modulate nociceptive processing in the TCC modulatory inputs. The PAG is considered to act largely via its connections with the rostral ventromedial medulla (RVM). In addition to the TCC modulatory inputs, local thalamic modulation of ascending trigeminothalamic projections also occurs. TG, trigeminal ganglion.

The Hypothalamus

Hypothalamic activation was originally associated with the trigeminal autonomic cephalalgias, including cluster headache (Matharu, Cohen, Frackowiak, & Goadsby, 2006; Matharu et al., 2004; May, Bahra, Buchel, Frackowiak, & Goadsby, 1998; May, Bahra, Buchel, Turner, & Goadsby, 1999); however, it is now well established that it is activated during the earliest premonitory phases of migraine (Maniyar, Sprenger, Monteith, Schankin, & Goadsby, 2014; Schulte & May, 2016), during the headache phase (Denuelle, Fabre, Payoux, Chollet, & Geraud, 2007; Sprenger, Maniyar, Monteith, Schankin, & Goadsby, 2012), and remains active even after the attenuation of the headache with sumatriptan (Denuelle et al., 2007). The hypothalamus has reciprocal connections with the trigeminocervical complex (Malick & Burstein, 1998; Malick et al., 2000; Robert et al., 2013), as well as important projections terminating in the nucleus of the solitary tract, rostral ventromedial medulla, periaqueductal gray, and nucleus raphe magnus (Settle, 2000).

Given this widespread connectivity, a recent functional neuroimaging study identified potential important alterations in hypothalamic connectivity across the migraine phases (Schulte & May, 2016). During the interictal (attack-free) state, the hypothalamus showed greater coupling to the spinal trigeminal nucleus; however, as the patient progressed into the attack, this coupling switched to the periaqueductal gray, suggesting that the hypothalamus may act to differentially regulate descending modulation of trigeminovascular processing in a state-dependent manner (Graebner, Iyer, & Carter, 2015). In agreement with a pivotal role of the hypothalamus in the regulation of migraine-related head pain, a recent neuroimaging study has proposed a two-stage model for hypothalamic involvement in episodic and chronic migraine, respectively (Schulte, Allers, & May, 2017). In the premonitory phase and during episodic migraine, hypothalamic activation is observed in the more anterior regions; however, in those patients who have transitioned to chronic migraine (more than 15 headache days per month; Headache Classification Committee, 2018), the hypothalamic activation is observed in the more posterior regions. The authors hypothesized that different hypothalamic regions are involved in the initiation/triggering of attacks as compared to the maintenance of attacks during the chronic phase.

The differential role of the hypothalamus is supported by the widespread activation of several hypothalamic nuclei in response to dural nociceptive stimulation, including the posterior, anterior, ventromedial, and paraventricular regions (Benjamin et al., 2004; Malick et al., 2001). As such, dysregulation of hypothalamic nuclei with important roles in descending modulation of trigeminal nociceptive activation and homeostatic regulation may shift the threshold for attack initiation, facilitating the transition from a more episodic state to a chronic state. Such divergent effects of altered hypothalamic function have been demonstrated preclinically in rodents.

Within the posterior hypothalamic region, Bartsch et al. demonstrated that dysregulation of orexinergic neural networks that project widely in the central nervous system (Peyron et al., 1998), including the periaqueductal gray, locus, coeruleus and trigeminocervical complex, can have divergent effects on trigeminal nociceptive processing (Bartsch, Levy, Knight, & Goadsby, 2004). Local posterior hypothalamic microinjection of orexin A demonstrated an antinociceptive effect, and orexin B conversely induced a pronociceptive effect on trigeminocervical nociceptive processing.

In agreement with this, Robert et al. further identified a similar bidirectional regulation of trigeminovascular processing from the paraventricular nucleus of the hypothalamus (Robert et al., 2013). The paraventricular nucleus has direct projections to the superior salivatory nucleus (regulating parasympathetic outflow to the face) and the superficial dorsal horn of the trigeminocervical complex. Gamma-aminobutyric acid (GABAA) and serotonin receptor 1B/D (5-HT1B/D) agonists along with pituitary adenylate cyclase–activating peptide antagonists microinjected into the paraventricular nucleus inhibited trigeminovascular activation, while GABAA antagonists and pituitary adenylate cyclase–activating peptide facilitated trigeminovascular activation. Of particular importance to migraine, the modulatory effects were state dependent, in that exposure of the rats to acute restraint stress decreased the GABAA-mediated inhibitory effects, with no impact on the facilitation. As such, the hypothalamus may play a key role in state-dependent regulation (e.g., in response to alterations in stress perception; Lipton et al., 2014) of migraine susceptibility .

The hypothalamus is established as the master regulator of homeostatic mechanisms, responding to several internal (e.g., energy balance; Waterson & Horvath, 2015) and external (e.g., light/dark cycles; Buijs & Vargas, 2017) cues to optimize state-dependent behavioral outputs. The common occurrence of hypothalamic-related perturbations such as altered appetite regulation (Parker & Bloom, 2012); sleep–wake states (Holland, 2014); nociceptive processing (Bartsch, Levy, et al., 2004; Holland & Goadsby, 2009; Robert et al., 2013); and bodily fluid balance (Thorn, 1970) further highlight its prominent role in migraine. This is supported by the recent emergence of a potential role for circadian dysregulation in migraine (Brennan et al., 2013; Holland, Barloese, & Fahrenkrug, 2018; van Oosterhout et al., 2018), under the control of the hypothalamic master clock in the suprachiasmatic nuclei (Hastings, Maywood, & Brancaccio, 2018), as well as differential trigeminovascular modulation via hypothalamic-mediated neuroendocrine signaling (Martins-Oliveira et al., 2017).

The Brainstem

The brainstem, and more specifically the periaqueductal gray, rose to prominence in relation to migraine when Weiller et al. identified that the dorsal midbrain was activated during spontaneous attacks (Weiller et al., 1995). It was then further demonstrated that this activation was independent of ongoing trigeminal pain because it remained after triptan-induced pain normalization (Denuelle et al., 2007). Several studies have now confirmed brainstem activation in the region of the periaqueductal gray (Afridi, Giffin, et al., 2005; Afridi, Matharu, et al., 2005; Bahra, Matharu, Buchel, Frackowiak, & Goadsby, 2001; Denuelle et al., 2007; Maniyar et al., 2014). Recently a potential role for the periaqueductal gray in chronic migraine has been highlighted because of increased iron deposition in the periaqueductal gray of patients with chronic migraine as compared to episodic migraineurs or healthy controls (Dominguez et al., 2019; Welch, Nagesh, Aurora, & Gelman, 2001).

In agreement with a frequency-dependent alteration in periaqueductal gray function, patients with a higher frequency of migraine attacks demonstrated increased periaqueductal gray connectivity with higher order cortical structures involved in pain perception and decreased connectivity with higher order structures, such as the prefrontal cortex involved in descending pain modulation (Dahlberg et al., 2018). This potential periaqueductal gray involvement was further associated with the presence of cranial allodynia during attacks; individuals reporting greater allodynia demonstrated significantly reduced volumes of midbrain regions, including the periaqueductal gray, compared to healthy controls (Chong, Plasencia, Frakes, & Schwedt, 2017).

The periaqueductal gray has reciprocal connections with higher order (cortical, thalamic, and hypothalamic); brainstem (medullary dorsal horn and rostral ventromedial medulla); and the trigeminocervical complex (Hoskin, Bulmer, Lasalandra, Jonkman, & Goadsby, 2001; Keay & Bandler, 1998; Oliveras, Woda, Guilbaud, & Besson, 1974). Experimental evidence demonstrated distinct activation of the ventrolateral periaqueductal gray in response to noxious durovascular stimuli, while altered periaqueductal gray signaling can modulate trigeminovascular processing (Knight, Bartsch, & Goadsby, 2003; Knight, Bartsch, Kaube, & Goadsby, 2002; Knight & Goadsby, 2001). Local ventrolateral periaqueductal gray microinjection of CGRP enhanced trigeminovascular nociception (Pozo-Rosich, Storer, Charbit, & Goadsby, 2015), whereas the clinically relevant blockade of CGRP and activation of 5-HT1B/D receptors was inhibitory (Bartsch, Knight, & Goadsby, 2004; Pozo-Rosich et al., 2015).

Although the exact circuitry of the periaqueductal gray’s antinociceptive role in migraine remains to be fully elucidated, it is likely via the periaqueductal gray–rostral ventromedial medulla circuitry. This was supported by a study that identified altered rostral ventromedial medulla to trigeminocervical complex functional connectivity in the period immediately before attack onset. Between attacks, during the interictal phase migraineurs conversely demonstrated increased functional connectivity (Marciszewski et al., 2018), highlighting that alterations in specific brainstem nuclei may represent a key stage in the initiation of migraine attacks. The rostral ventromedial medulla receives reciprocal projections from the periaqueductal gray (Basbaum, Clanton, & Fields, 1978) and is ideally positioned to modulate bidirectionally trigeminal nociceptive processing. “On” and “off” cells in the rostral ventromedial medulla provide descending modulation of trigeminal nociception, experimental inflammation of the dura mater potentiates the activity of on cells, while off cells are acutely inhibited (Edelmayer et al., 2009). Further, cephalic and extracephalic allodynia development in response to dural inflammatory-mediated central sensitization can be inhibited by direct blockade of the rostral ventromedial medulla.

Thus, direct modulation of the rostral ventromedial medulla can inhibit trigeminal and spinal nociception. However, it should be noted that the rostral ventromedial medulla projects bilaterally to all levels of the spinal cord, and as such it is difficult to reconcile a specific role in head pain processing, especially given the prominent unilateral nature of many primary headaches (Afridi, Matharu, et al., 2005).

As described previously, migraine attacks are commonly preceded by an array of premonitory features, including marked fatigue (Giffin et al., 2003). While the specific mechanisms for these premonitory symptoms remain to be fully characterized, the locus coeruleus has emerged as a key neural hub. It is the principle site of norepinephrine synthesis in the brain (Schwarz & Luo, 2015) and receives projections from the paraventricular and lateral hypothalamic nuclei (Reyes, Valentino, Xu, & Van Bockstaele, 2005), the latter of which represent the densest orexinergic projections from the hypothalamus (Peyron et al., 1998), which is considered to act by promoting activity in the ascending arousal network to promote wakefulness. In turn, the orexinergic neurons receive direct inputs from the lateral parabrachial nucleus (Arima, Yokota, & Fujitani, 2019), suggesting a potential network for the integration of sensory/discriminative pain processing and vigilance.

This is in keeping with a recent study that identified further state-dependent regulation of freezing behaviors in mice (Soya et al., 2017). Activation of locus coeruleus noradrenergic to lateral amygdala projections that receive direct orexinergic inputs increased freezing behaviors, whereas inhibition of this pathway diminished this response (Soya et al., 2017). Importantly, prior fasting of mice, which results in increased orexinergic tone, was able to potentiate the freezing behaviors, suggesting that dysfunction of this hypothalamic brainstem network may link homeostatic challenges (e.g., energy balance) to altered nociceptive processing.

With respect to trigeminovascular nociceptive processing, electrical lesioning of the locus coeruleus demonstrated robust reductions in durovascular-evoked nociceptive processing in the trigeminocervical complex, which was mimicked by local activation of α2 adrenoceptors (Vila-Pueyo, Strother, Kefel, Goadsby, & Holland, 2019). In contrast, α1-adrenoceptor activation was pronociceptive, in agreement with prior experiments that highlighted divergent effects of locus coeruleus modulation on pain (Drummond, 2012; Hickey et al., 2014). In addition to the effects on nociception, chronic ablation of the locus coeruleus increased the susceptibility of rats to cortical spreading depression (Vila-Pueyo et al., 2019), the electrophysiological correlate of migraine aura (Charles, 2018). Given the specific arousal-related mechanisms of the locus coeruleus (Carter et al., 2010) and its regulation by the sleep–wake regulating orexinergic neurons (Soya et al., 2017), the studies mentioned suggest a potential link between the regulation of sleep and migraine (Brennan & Charles, 2009; Holland, 2014) that is supported by their clinical and pathophysiological interactions (Holland, 2014).

Potential Modulation of Trigeminovascular Processing by Cortical Spreading Depression

As noted previously, in approximately 25%–30% of patients, attacks can occur in conjunction with migraine aura (Headache Classification Committee, 2018), most commonly presenting as transient visual disturbances, but motor or somatosensory symptoms may occur. While the exact role for aura in migraine remains a fiercely debated topic in the field (Charles, 2018), recent evidence has emerged demonstrating that cortical spreading depression, which is the accepted underlying mechanism of aura, can have direct actions on trigeminovascular nociceptive processing (X. Zhang et al., 2011). Cortical spreading depression is a slowly moving depolarizing wave that propagates across the cortex, impacting neural, glial, and vascular functions with resultant suppression of activity (Kramer, Fujii, Ohiorhenuan, & Liu, 2016).

With respect to the local microenvironment, cortical spreading depression results in dysregulation of adenosine triphosphate (ATP), glutamate, potassium, nitric oxide, and CGRP dynamics (Enger et al., 2015). It is known that in rats a single cortical spreading depression event can lead to both acute and prolonged increases in trigeminovascular activity (X. Zhang et al., 2011), and that this increased activation can be prevented by targeted inhibition of CGRP mechanisms (Melo-Carrillo et al., 2017). Interestingly, CGRP does not trigger aura in patients with migraine with aura or those with familial hemiplegic migraine (Hansen, Hauge, Olesen, & Ashina, 2010; Hansen, Thomsen, Olesen, & Ashina, 2011); this is in agreement with preclinical data demonstrating that CGRP receptor blockers inhibit pain behaviors evoked by cortical spreading depression with no effect on the cortical spreading depression propagation or hemodynamic response (Filiz et al., 2019), despite potential CGRP and CGRP receptor involvement in cortical spreading depression ex vivo (Tozzi et al., 2012). In comparison, the majority of other nonspecific prophylactic therapies for migraine showed a clear effect in reducing cortical spreading depression frequency (Costa et al., 2013).

While the direct link between cortical spreading depression and trigeminovascular activation remains debated, one study (Tozzi et al., 2012) postulated a potential mechanism for recurrent cortical spreading depression induced activation of meningeal nociceptors. Mice exposed to repeated cortical spreading depression’s demonstrated opening of neuronal pannexin 1 megachannels, resulting in the release of pro-inflammatory molecules from neurons and astrocytes (Karatas et al., 2013). Importantly, suppression of this pannexin 1–dependent cascade inhibited cortical spreading depression–induced increased trigeminovascular activation, suggesting the possibility that cortical spreading depression could act to promote trigeminal-mediated nociception in migraine with aura.

Modulation of Trigeminovascular Processing by the Human Migraine Trigger Nitroglycerin

Nitroglycerin has emerged as the most prominent exogenous trigger for delayed migraine-like attacks in patients (Ashina, Hansen, Á Dunga, & Olesen, 2017). Initially known for its ability to trigger migraine-related headache, it is now understood that nitroglycerin can induce a diverse array of migraine-related symptoms, including premonitory symptoms and cutaneous allodynia (Afridi, Kaube, & Goadsby, 2004; Akerman et al., 2019). Functional magnetic resonance imaging studies have identified increased activity in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal gray, dorsal pons, and several cortical regions during nitroglycerin-triggered premonitory symptoms (Maniyar et al., 2014). Despite the abundance of its use, the exact mechanism of action of nitroglycerin and other clinically used migraine triggers remains unknown (Ashina et al., 2017).

Preclinically, the use of nitroglycerin to model migraine-related phenotypes and therapeutic potential has grown considerably, with both acute and chronic administration models developed (Demartini et al., 2019). Initial studies in rodents highlighted a progressive reduction in hind paw (Bates et al., 2010) and subsequently orofacial (Farkas et al., 2016) withdrawal thresholds in response to nitroglycerin, while more recently a dose-dependent sensitivity has been highlighted for transgenic migraine-relevant mouse models. For example, mice harboring the human loss-of-function mutation of casein kinase 1 delta that is responsible for familial advanced sleep phases and comorbid migraine with aura demonstrated an increased sensitivity to 5 mg/kg nitroglycerin, while their wild-type littermates did not respond at this dose (Brennan et al., 2013).

Given the ongoing debate about the role of the peripheral versus central mechanisms of migraine and other pain disorders (Eller-Smith, Nicol, & Christianson, 2018), much of the focus on nitroglycerin has centered on potential changes in the trigeminal ganglion. Recently, a multiphasic effect of nitroglycerin was demonstrated in mice (Marone et al., 2018), whereby initial increases in nitric oxide subsequently led to the generation of increased reactive oxygen and carbonyl species within the trigeminal ganglion. The prolonged hypersensitivity was transient receptor potential cation channel, subfamily A, member 1 dependent via the generation of nicotinamide adenine dinucleotide phosphate oxidase 1 and 2. This interesting study highlighted a potential divergent role for nitroglycerin in the modulation of trigeminovascular processing, with acute nitric oxide resulting in early sensitization of trigeminal afferents that may explain the mild initial headache observed in patients (Ashina et al., 2017), while alternate downstream mechanisms were critical for driving the prolonged hypersensitivity akin to the delayed migraine-like attacks in patients.

Physiologically, the nitroglycerin-evoked hypersensitivity has been associated with increased trigeminovascular activation (Akerman et al., 2019). Intravenous nitroglycerin evokes a delayed sensitization of spontaneous and durovascular nociceptive-evoked trigeminocervical complex neuronal responses in rats, with increased Aδ- and C-fiber responses. Crucially, second-order trigeminocervical complex ascending neurons that initially only responded with Aδ latencies demonstrated the unmasking of a C-fiber response following nitroglycerin. This trigeminovascular sensitization was triptan sensitive, being inhibited by naratriptan, which is in agreement with clinical data showing that nitroglycerin-induced migraine-like attacks were triptan sensitive (Akerman et al., 2019).

With respect to the potential site of action of nitroglycerin, a recent imaging study utilizing ultrahigh-field sodium imaging identified early changes in sodium concentrations in the brainstem and extracerebral cerebrospinal fluid prior to the onset of mechanical hypersensitivity (Abad, Rosenberg, Hike, Harrington, & Grant, 2018). This is in agreement with the human neuroimaging data, with key brainstem regions active during the premonitory phase of nitroglycerin-triggered attacks (Maniyar et al., 2014).

While not discussed in detail in this chapter, there is growing evidence for the utility of a number of human migraine triggers in preclinical models, including CGRP (Mason et al., 2017; Wattiez, Wang, & Russo, 2019) and cilostazol (Christensen, Petersen, Sorensen, Olesen, & Jansen-Olesen, 2018), although nitroglycerin remains the most commonly utilized.

Recent Advances in Migraine Therapy

As detailed previously in this chapter, migraine is one of the most disabling neurological disorders globally (Steiner et al., 2018); however, the high prevalence and economic and quality-of-life impact were not fully matched by the available therapeutic options. Multiple analgesic compounds, including the nonsteroidal anti-inflammatory drugs, paracetamol (acetominophen), and unfortunately opioids, were commonly used for acute attack resolution (Ong & De Felice, 2018). More specific to migraine, compounds targeting serotonergic signaling, such as ergotamine, demonstrated clinical efficacy (P. Tfelt-Hansen et al., 2000) and ultimately paved the way for the development of the first specific acute migraine drugs (Humphrey et al., 1990), the triptans (Ong & De Felice, 2018). Despite this success, the triptans were only effective in up to 40% of patients, and prophylactic therapies largely consisted of a plethora of divergent compounds, from beta-blockers to anticonvulsants, with considerable side-effect profiles (Sprenger, Viana, & Tassorelli, 2018).

More recently, building on the increased understanding of the underlying mechanisms of migraine and the neuropeptides/neurotransmitters involved in its pathophysiology, migraine therapy is undergoing a renaissance. The remainder of this chapter discusses this remarkable progression with three novel therapeutic options either clinically approved or successfully completed Phase III clinical trials.

Ditans-5-HT1F Receptor Agonists

Sumatriptan, the first triptan developed, and naratriptan target the serotonin 5-HT1B, 5-HT1D, and 5-HT1F receptors, while other triptans, including rizatriptan, have no efficacy for the 5-HT1F receptor at all (Rubio-Beltran, Labastida-Ramirez, Villalon, & MaassenVanDenBrink, 2018). While initially considered to act via vasoconstrictive mechanisms (Humphrey & Feniuk, 1991), it is now understood that their mechanism of action is largely neural, via the 5-HT1D or 5-HT1B receptor (Donaldson, Boers, Hoskin, Zagami, & Lambert, 2002) and partial 5-HT1F effects (Goadsby & Classey, 2003). However, several contraindications remain due to potential vascular effects (D. Dodick et al., 2004).

Importantly, the identification of potential 5-HT1F receptor mechanisms for selected triptans led to the development of targeted 5-HT1F receptor agonists (ditans) (Vila-Pueyo, 2018). To date, several ditans have been developed, including lasmiditan (LY573144 or COL-144), LY334370, LY349950, and LY344864. Both lasmiditan and LY334370 have demonstrated clinical efficacy (Goadsby et al., 2019; Goldstein et al., 2001; Kuca et al., 2018); however, the development of LY334370 was halted due to off-target toxicology issues in dogs (Rizzoli, 2014).

As such, the review focuses on lasmiditan as it remains the most clinically advanced ditan. 5-HT1F receptor messenger RNA (mRNA) is widely expressed throughout the central and peripheral nervous systems, including in key regions of the trigeminovascular system (cortex, thalamus, periaqueductal gray, locus coeruleus, trigeminocervical complex, and trigeminal ganglia), with limited (cerebral blood vessels, coronary artery) or no vascular expression (heart) (Bouchelet, Cohen, Case, Seguela, & Hamel, 1996; Castro et al., 1997; Classey, Bartsch, & Goadsby, 2010; Fugelli, Moret, & Fillion, 1997; Lucaites, Krushinski, Schaus, Audia, & Nelson, 2005; Ma, 2001; Wainscott et al., 2005). Of particular note, lasmiditan crosses the blood–brain barrier, unlike many acute therapies that show only limited or no central access (Kaube, Hoskin, & Goadsby, 1993; Schankin et al., 2016; P. C. Tfelt-Hansen, 2010). Experimentally, this potential central site of action is supported by the ability of intravenously administered LY344864 to inhibit trigeminocervical complex neuronal responses to intracisternal capsaicin in rodents (Mitsikostas, Sanchez del Rio, & Waeber, 2002). While neuronal responses in the trigeminocervical complex that result from durovascular nociceptive activation (potential peripheral or central mechanisms) are also dose-dependently decreased via 5-HT1F mechanisms (Goadsby & Classey, 2003; Shepheard et al., 1999).

In addition to their clear neuronal effects, lasmiditan and other 5-HT1F receptor agonists potently block plasma protein extravasation from the meninges (Johnson et al., 1997; Phebus et al., 1997). However, this mechanism is likely not related to their clinical efficacy, given the lack of efficacy of multiple plasma protein extravasation inhibitors in migraine (Connor, Bertin, Gillies, Beattie, & Ward, 1998; Goldstein et al., 1997).

While holding significant promise as a novel therapy for migraine, it must be noted that there is no evidence for a potential role of 5-HT (Connor et al., 1998; Goldstein et al., 1997) agonists in pain more generally, as LY334370 failed to inhibit carrageenan-induced hind paw hyperalgesia (Shepheard et al., 1999). This apparent specific ability to inhibit trigeminal-mediated pain processing has been attributed to a potential role in inhibiting CGRP release, with both lasmiditan and sumatriptan demonstrating efficacy at reducing CGRP release from the trigeminovascular afferents at the level of the dura mater, trigeminal ganglion, and trigeminocervical complex (Amrutkar et al., 2012; Labastida-Ramirez et al., 2017). The importance of targeting CGRP signaling in migraine therapy is discussed further in this chapter.

Clinically, lasmiditan has now completed two Phase III trials for migraine, both of which have demonstrated clinical efficacy and good tolerability with limited adverse events (Wietecha, Kuca, Asafu-Adjei, & Aurora, 2018). A dual-dosing study (SAMURAI; 100 and 200 mg daily; Kuca et al., 2018) with over 700 migraine sufferers receiving each dose and placebo lasmiditan demonstrated improved 2-hour pain-free rates at 100- and 200-mg doses (28.2% and 32.2%, respectively) when compared to placebo (15.3%). In addition to the 2-hour pain-free endpoints, the study utilized the most bothersome symptom outcome newly approved by the Food and Drug Administration (FDA), with patients reporting their most bothersome symptom, most commonly photophobia. In agreement with the pain-free data, both 100- and 200-mg doses (40.9% and 40.7%, respectively) reported a significant reduction in their most bothersome symptom as compared to those receiving the placebo (29.5%). A second Phase III trial (SPARTAN; Goadsby et al., 2019) demonstrated similar increased efficacy (38.8%) for 200-mg lasmiditan on 2-hour pain-freedom rates compared to placebo (21.3%) and 48.7% versus 33.5% for the most bothersome symptom. Across both Phase III trials, lasmiditan was well tolerated with common adverse events including dizziness, fatigue, lethargy, nausea, paresthesia, and somnolence; a third open-label observational study is ongoing (GLADIATOR, NCT02565186).

Targeted Modulation of CGRP Signaling for Migraine

The CGRP pathway has emerged as a breakthrough therapeutic target for the acute and prophylactic treatment of migraine (Holland, 2018). CGRP, a polypeptide with 37 amino acids, is a member of the calcitonin family, with αCGRP and βCGRP synthesized from CALC I and CALC II, respectively (Amara et al., 1985). Given the predominance of αCGRP in the central and peripheral nervous systems, the neurobiology of αCGRP signaling in migraine is discussed. As outlined previously in this chapter, the trigeminal afferents arising in the trigeminal ganglion are mostly thinly myelinated Aδ and unmyelinated C fibers. Approximately 50% of all cell bodies located in human and rodent trigeminal ganglion express CGRP (Eftekhari et al., 2010) along with other neuropeptides, such as substance P, neurokinin A, nitric oxide synthase, and pituitary adenylate cyclase–activating polypeptide (Figure 2). Calcitonin gene–related peptide is generated by the cleavage of the precursor protein originating from splicing of mRNA from the CALC I gene (Quirion, Van Rossum, Dumont, St-Pierre, & Fournier, 1992).

Like all neuropeptide signaling, CGRP is generated at the cell body and packed into dense core vesicles, which are then shuttled to the axon terminals to be released (Harmann, Chung, Briner, Westlund, & Carlton, 1988). On release via calcium-dependent exocytosis, there is no local reuptake mechanism similar to that seen for fast neurotransmitter signaling, and as such CGRP can diffuse away from the axon terminal, working both locally (micrometer range) on the postsynaptic neuron and more remotely (millimeter range) on neurons and associated satellite glial cells. In the trigeminovascular system, the pseudounipolar nature of the trigeminal afferents leads to neuropeptide release from the afferents innervating the face and durovasculature (Goadsby, Holland, et al., 2017), which underlies the failed rationale for the development of neurogenic inflammation blockers for migraine (May & Goadsby, 2001). Centrally, the release of CGRP acts to modulate the sensitivity of second-order ascending trigeminal projections, while CGRP release locally within the ganglion has been linked to the modulation of sensory processing, likely via an interaction with local satellite glial cells in a volume transmission manner (Iyengar, Ossipov, & Johnson, 2017).

The initial observation of a potential role for CGRP in migraine surfaced relatively soon after CGRP was first discovered. Edvinsson and Goadsby demonstrated that both CGRP and pituitary adenylate cyclase–activating peptide were elevated in patients during spontaneous migraine attacks (Goadsby & Edvinsson, 1993; Zagami, Edvinsson, & Goadsby, 2014); however, there was no change in substance P levels. This was further supported by the preclinical observation of similar neuropeptide changes in cats following stimulation of the trigeminal ganglion or durovasculature, specifically the superior sagittal sinus and its trigeminal innervation (Goadsby & Edvinsson, 1993). The release of CGRP in the trigeminocervical complex is thought to be regulated by presynaptic mechanisms on the trigeminal afferents, with 5-HT1B and 5-HT1D receptor agonists able to inhibit CGRP release. This is supported by both clinical and preclinical data, whereby the 5-HT1B and 5-HT1D receptor agonist sumatriptan was able to normalize the elevated CGRP levels observed in patients and dose-dependently inhibit potassium chloride–induced CGRP release from trigeminal ganglion cultures (Goadsby & Edvinsson, 1993; Iyengar et al., 2017). When combined with recent experimental data demonstrating that CGRP can trigger delayed migraine-like attacks in patients on a timescale that goes beyond its simple vasodilator mechanisms (Hansen et al., 2010), it is clear that CGRP-mediated sensitization of the trigeminovascular system is a key potential mechanism for migraine therapy.

The CGRP Receptor System

The CGRP receptor is a seven transmembrane G protein–coupled receptor consisting of the calcitonin-like receptor (CLR) and its interaction with the receptor activity–modifying protein 1 (Hay & Walker, 2017). However, similar related receptors exist consisting of the calcitonin receptor (CTR) and associated receptor activity–modifying proteins. This relative complexity of receptor components gives rise to the CGRP (CLR/RAMP-1) and amylin 1 (AMY; CTR/RAMP-1) receptors with varying responses to CGRP in vitro and ex vivo (Hay, 2018). The interaction of the CTR with receptor activity–modifying protein 1 is termed the AMY1 receptor, while the interaction of the CTR with receptor activity–modifying proteins 2 and 3 gives rise to the AMY2 and AMY3 receptors, respectively. CLR with receptor activity–modifying proteins 2 and 3 gives rise to the adrenomedullin AM1 and AM2 receptors, respectively, and finally the CTR can act independently (Lee, Hay, & Pioszak, 2016).

The functional relevance of the complex receptor family remains to be fully elucidated; however, it is clear that the interface between CLR and receptor activity–modifying protein 1 is necessary for CGRP binding and response, although the AMY1 receptor has shown affinity for CGRP in vitro (Hay, Poyner, & Smith, 2003). The CGRP receptor additionally couples to a G protein Gs α subunit, which leads to increased cyclic adenosine monophosphate (cAMP) production and a receptor coupling protein that acts to promote the G protein signaling mechanism. This activation of CGRP receptors can result in diverse signaling cascades, including G protein–coupled receptor kinase-dependent phosphorylation, leading to desensitization and internalization of the receptor and protein kinase A–/protein C–dependent desensitization. It is noteworthy that recent data have highlighted potential continued signaling from internalized G protein–coupled receptors via endosomes (Yarwood et al., 2017), which would in theory result in active receptors that were inaccessible to current therapies. It remains to be seen if such mechanisms could have clinical relevance with respect to targeting the CGRP receptor directly or indirectly via CGRP itself.

Small-Molecule CGRP Antagonists

To date, several CGRP-targeted small-molecule antagonists have been developed for the acute treatment of migraine; the first clinically tested was BIBN4096 (olcegepant). Olcegepant potently inhibits the binding of CGRP to the CGRP receptor in picomolar concentrations. Initial observations focused on its ability to inhibit vasodilation evoked by trigeminovascular activation or exogenous CGRP administration (Kapoor et al., 2003; Petersen, Birk, Doods, Edvinsson, & Olesen, 2004; Troltzsch, Denekas, & Messlinger, 2007); however, as detailed previously in this chapter, the acceptance of a limited role for vasodilation in migraine (Amin et al., 2013) led to a more neural-focused mechanism. In agreement with the release of CGRP from primary afferents terminating in the trigeminocervical complex, systemically administered olcegepant was able to inhibit trigeminocervical complex neuronal activation induced by capsaicin with little or no impact of trigeminal ganglion activation (Sixt, Messlinger, & Fischer, 2009; Storer, Akerman, & Goadsby, 2004).

In support of a central site of action it was further demonstrated that local iontophoretic application of olcegepant in the trigeminocervical complex could modulate durovascular-evoked trigeminocervical complex neuronal responses in the cat (Storer et al., 2004). This central versus peripheral mechanism remains a keenly debated topic in the field (P. Tfelt-Hansen & Olesen, 2011). On one side, currently available therapies have limited blood–brain barrier penetrability (see further section on monoclonal antibodies), while on the other side, centrally administered olcegepant can modulate trigeminovascular activity when given globally into the cerebrospinal fluid circulation (Recober et al., 2009) or when administered locally in key migraine-related nuclei, including the thalamus (Summ, Charbit, Andreou, & Goadsby, 2010) and periaqueductal gray (Pozo-Rosich et al., 2015).

Despite this potential central mechanism, it is now widely accepted that the trigeminal ganglion likely represents a key initial site of action of antimigraine therapeutics due to its presence outside the blood–brain barrier. The key stepwise change in the field occurred in 2004, with the completion of the first clinical trials for olcegepant in the acute treatment of migraine (Olesen et al., 2004). Following the completion of initial safety studies, a seminal study by Olesen and colleagues identified that olcegepant resulted in significant headache relief in 66% of patients as compared to 27% of controls at 2 hours after treatment.

The success of this study coupled with the poor bioavailability of olcegepant led to the development of several small-molecule antagonists targeting the CGRP receptor (gepants) (Holland & Goadsby, 2018). These new gepants were designed to have greater oral bioavailability and increased potency compared to olcegepant, including telcagepant, rimegepant, ubrogepant, atogepant, MK-3207, and MK-8825.

With respect to potential central nervous system sites of action of the gepants, [3H]MK-3207 binding has been demonstrated in several brain regions of the rhesus monkey highlighted previously in Pathophysiology of Head Pain Pathways section, specifically the hypothalamus, periaqueductal gray, dorsal raphe nucleus, and spinal trigeminal nucleus (Eftekhari et al., 2016). Akin to olcegepant, MK-8825 has demonstrated preclinical efficacy in rodent models of cortical spreading depression–induced pain behaviors (Filiz et al., 2019) and nitroglycerin-induced trigeminocervical complex activation (Feistel, Albrecht, & Messlinger, 2013) and hyperalgesia (Greco et al., 2014), while having no impact on cortical spreading depression induction (Filiz et al., 2019). Translationally, this supports a divergent neurobiology for migraine and cortical spreading depression/migraine aura whereby CGRP is unable to trigger migraine aura in patients (Guo, Vollesen, Olesen, & Ashina, 2016; Hansen et al., 2010), with only migraine without aura experienced.

However, preclinically there were conflicting results. The CGRP receptor antagonist MK-8825 demonstrated no effects on cortical spreading depression in vivo (Filiz et al., 2019) despite attenuating its potential modulation of the trigeminovascular system. Yet, the CGRP receptor antagonists MK-8825, olcegepant, and CGRP8-37 all inhibited cortical spreading depression in rat neocortical slices (Tozzi et al., 2012).

The majority of the gepants that have progressed to clinical trials have generated positive results, highlighting the importance for CGRP for the neurobiology of migraine-related pain. Despite this remarkable consistent efficacy, only rimegepant (Lipton, Coric, et al., 2018; Marcus et al., 2014) and ubrogepant (D. W. Dodick et al., 2018; Lipton, Dodick, et al., 2018; Voss et al., 2016) remain in active clinical development for acute migraine therapy and atogepant (clinical trial NCT03855137) for migraine prophylaxis (Goadsby et al., 2018) due to the emergence of potential off-target liver enzyme issues following longer term usage of specific gepants (Ho et al., 2014).

CGRP Monoclonal Antibodies

Emerging from the development of the gepants and their success in migraine prevention (Ho et al., 2014, 2016), and in response to the off-target side effects of telcagepant and MK-3207, attention shifted toward the development of CGRP-targeted monoclonal antibodies (Raffaelli & Reuter, 2018). To date, four antibodies have been developed, with one targeting the CGRP receptor (erenumab) and three targeting the neuropeptide itself (eptinezumab, galcanezumab, and fremanezumab). Biologically, the differentiation between the targets is an interesting one for the neurobiology of migraine. As highlighted previously in the chapter the receptor pharmacology for CGRP is complex, with potential differential receptors (CGRP and AMY1) responsive to CGRP (Hay, 2018; Hay & Walker, 2017; Lee et al., 2016).

Preclinically, there is limited published data on the monoclonal antibodies targeting CGRP or its receptor; however, initial studies have emerged. As detailed in this chapter, cortical spreading depression, the electrophysiological correlate of migraine aura, has been shown to result in the sensitization of trigeminovascular neurons (X. Zhang et al., 2011) in rodents. The cortical spreading depression–mediated sensitization of trigeminal afferents was prevented by fremanezumab (Melo-Carrillo et al., 2017) without inhibition of the cortical spreading depression itself. In agreement with the ability of CGRP to trigger migraine attacks in migraineurs (Hansen et al., 2010), intraperitoneal administration of CGRP in mice resulted in spontaneous pain behaviors that were inhibited by the rodent-specific anti-CGRP monoclonal antibody ALD405 (Rea et al., 2018). Further, ALD405 has also been shown to block CGRP-induced photophobic-like behavior in mice (Mason et al., 2017), suggesting an action on the convergence of dural and light-sensitive afferents in the trigeminovascular system (Noseda et al., 2010).

Clinically, a number of monoclonal antibodies targeting CGRP or its receptor have completed Phase I–III trials (Mitsikostas & Reuter, 2017). Provisional data from a Phase III trial of eptinezumab on 888 patients receiving 30, 100, or 300 mg every 3 months highlighted on average nearly 50% reduction in monthly migraine days from 8.5 to 4.5, 4.6, and 4.2, respectively over the 12-week period (Saper et al., 2017). In a dual-dosing study of erenumab (placebo, 70 or 140 mg monthly for 6 months; Goadsby, Reuter, et al., 2017) in 955 patients, suffering from a mean of 8.3 migraine days per month, erenumab resulted in a reduction in mean migraine days to 5.1 and 4.6 in the 70- and 140-mg groups, respectively, compared to 6.5 in the placebo. A 50% reduction in migraine days was observed in 43.3% of the 70-mg group and 50% of the 140-mg group, compared to 26.6% of the placebo group, with a concomitant reduction in days of acute medication use of 1.1, 1.6, and 0.2 days, respectively.

Of particular importance for migraineurs, a Phase IIIb study of 246 patients who had previously failed to respond to at least two migraine preventives (Reuter et al., 2018) demonstrated that following 12 weeks of erenumab, 30% of patients experienced a reduction of 50% or greater in migraine days, compared to 14% for placebo. As such, it is proposed that prior failure of preventive medication does not impact the efficacy of targeted CGRP prophylaxis.

With respect to chronic migraine (headache days on greater than 15 days per month), both galcanezumab (Detke et al., 2018) and fremanezumab (Silberstein et al., 2017; VanderPluym et al., 2018) results have been published. In a large trial of 1,130 patients receiving fremanezumab (Silberstein et al., 2017) monthly, quarterly or placebo, patients experienced a reduction in migraine days of 4.6, 4.3, and 2.5, respectively. A 50% reduction in migraine days was observed in 41% of the monthly group, 38% of the quarterly group, and 18% of the placebo group, suggesting that quarterly administration may be as effective as monthly dosing. Finally, galcanezumab administered at a dose of 120 mg (following an initial 240-mg loading dose), 240 mg, or placebo per month in a cohort (N = 558) of patients with high-frequency chronic migraines (>19 attacks per month) demonstrated a reduction in the mean number of migraine days of 4.8, 4.6, and 2.7 respectively (Detke et al., 2018). The corresponding 50% responder rates were 27.6%, 27.5%, and 15.4%, respectively.

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