Headache Currents
HEADACHE CURRENTS
A Novel Translational Animal Model of Trigeminal Autonomic Cephalalgias Simon Akerman, PhD; Peter J. Goadsby, MD, PhD
Overview.—Trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders that involve severe unilateral head pain coupled with significant lateralized cranial autonomic features. Our understanding of these disorders and the development of novel and more effective treatments has been limited by the lack of a suitable animal model to explore their pathophysiology and screen prospective treatments. Discussion.—This review details the development of a novel preclinical model that demonstrates activation of both the trigeminovascular system and parasympathetic projections, thought to be responsible for the severe head pain and autonomic symptoms. Conclusion.—This model demonstrates a unique response to TAC specific treatments and highlights the importance of the cranial parasympathetic pathway to the pathophysiology of TACs and as a potential locus of action for treatments. The development of this model opens up opportunities to understand the pathophysiology of these disorders further, the likely involvement of the hypothalamus, as well as providing a preclinical model with which to screen novel compounds. Key words: trigeminal autonomic cephalalgias, brainstem, superior salivatory nucleus, parasympathetic outflow, triptans, oxygen
Trigeminal autonomic cephalalgias (TACs)1 are highly disabling primary headache disorders characterized by severe unilateral head pain, sometimes described as the worst pain experienced by humans, which occurs in association with ipsilateral cranial autonomic features.2 Their pathophysiology is characterized by 3 major clinical features: unilateral trigeminal distribution of pain, lateralized associated symptoms, including cranial autonomic features,3,4 and an episodic pattern of attacks.5,6 The TACs are differentiated from each other by their highly individual characteristic attack patterns, and also, to some extent, by their response to treatments. Cluster headache attacks tend to have the longest duration with lower attack frequency per day and seem to respond well to oxygen and sumatriptan treatment.7 Paroxysmal hemicrania has an intermediate duration and attack frequency per day and From the Headache Group, Department of Neurology, University of California, San Francisco, CA, USA (S. Akerman); NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, UK (P.J. Goadsby). Address all correspondence to S. Akerman, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Accepted for publication September 10, 2014. ............. Headache © 2015 American Headache Society
is specifically defined by its response to indomethacin.8 Shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) has the shortest duration and has many discrete attacks per day,9 while hemicrania continua has unremitting pain.10 These clinical features and treatments are summarized in Table 1 and reviewed in detail elsewhere.6,11,12 Our basic understanding of the pathophysiology of the TACs is emerging and has come mainly from clinical research and what is observed in clinic. A limitation to furthering our understanding of these severe headache disorders, and particularly in developing novel treatments, has been a lack of reliable, translational animal models. Preclinical animal models of headache have helped us understand the anatomy of the trigeminovascular and cranial autonomic systems, something that is shared in many headache disorders; but they mainly focus on understanding migraine pathophysiology. However, TACs have specific clinical features and response to treatments that separate them from migraine and other headache disorders, and therefore are likely to have a different pathophysiology, and require a specific animal model to understand them more fully. The advantages of a dedicated and specific animal model is that it will allow us to understand further their pathophysiology and, most importantly for the patient, to develop tailored therapies for their treatment. In this review, we describe our recently characterized animal model of TACs and the advantages this now carries in exploring the pathophysiology of TACs and the development of novel treatments.13,14
CLINICAL DATA What is known about TACs and how this may help us in developing an animal model comes partly from the very clear classification of these disorders; the combination of lateralization: of pain, associated features and cranial autonomic features, and some degree of tendency to episodic attacks.5,6 Clinical research reveals that there is activation in the region of the posterior hypothalamic gray matter during the pain in cluster headache,15 paroxysmal hemicrania,16 SUNCT,17,18 and hemicrania continua,19 and deep brain stimulation of this region can relieve cluster headache in some patients.20,21 Also, there is release of calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in cluster headache22 and chronic paroxysmal hemicrania.23 Furthermore, in experimental studies, capsaicin-induced pain in the ophthalmic division of the trigeminal nerve demon............. Conflict of Interest: S.A. none declared. P.J.G. has consulted with manufacturers of medical oxygen Air Products and Linde.
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Table 1.—Clinical Features and Treatments of Trigeminal Autonomic Cephalalgias Cluster Headache
Paroxysmal Hemicrania
SUNCT/SUNA
Sex F : M Pain type Severity Site Attack frequency Duration of attack Autonomic features
1:3 Stabbing, boring Excruciating Orbit, temple 1/alternate days – 8/day 15-180 minutes Yes
1:1 Throbbing, boring, stabbing Excruciating Orbit, temple 1-40/day (>5/day most of the time) 2-30 minutes Yes
Abortive treatments Preventive treatments
Sumatriptan, oxygen Verapamil, lithium
None Indomethacin (absolute response)
1:1.2 Burning, stabbing, sharp Severe to excruciating Periorbital 3-200/day 5-240 seconds Yes (mainly conjunctival injection and lacrimation-SUNCT) None Lamotrigine, topiramate, gabapentin
Table adapted from Cohen et al.11 SUNA = short-lasting unilateral neuralgiform headache; SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
strates many of the vascular changes that are present during TACs, but there is no hypothalamic activation.24 This has led to the hypothesis that the vascular changes taking place in TACs are likely a consequence of activation in the brain, potentially by a dysfunction or activation in the hypothalamus, particularly given the circadian rhythmicity of attacks, which is likely influenced by the suprachiasmatic nucleus. Therefore, in developing an animal model, it is important to consider a centrally mediated mechanism for activation of trigeminovascular and cranial autonomic pathways.
PRECLINICAL DATA To understand what is necessary of an animal model, it is also important to grasp the anatomy and physiology of the pathways involved. The excruciating trigeminal-distribution pain is likely to be a consequence of activation of the trigeminovascular system, including the peripheral afferent projection to the pain-producing cranial vessels of the dura mater and the central projection to the trigeminal nucleus caudalis and its extension to the cervical spinal cord, the trigeminocervical complex (TCC). Nociceptive activation of this pathway in animals has been shown to cause neuronal activation in the superior salivatory nucleus (SuS) within the pons,25 through the trigeminal autonomic reflex arc, and is the origin of cells for the cranial parasympathetic autonomic vasodilator pathway.26 This efferent projection is predominantly through the greater petrosal nerve, a branch of the facial (VIIth) cranial nerve, and its projection through the sphenopalatine (sometimes called pterygopalatine) ganglion.27 Autonomic symptoms in migraine are believed to result from activation of the trigeminal autonomic reflex arc to the SuS and its projection to the cranial vessels and lacrimal glands. A significant and defining feature in TACs is their lateralized cranial autonomic features, which include lacrimation, conjunctival injection, aural fullness, and nasal congestion and a local third-order sympathetic lesion
due to carotid swelling.28 Therefore, activation of this projection from the SuS is thought to play a far more significant role in TAC pathophysiology. The hypothalamus, as suggested by imaging studies during TACs, is clearly an important region in their pathophysiology. Anatomically, there are reciprocal connections between various nuclei of the hypothalamus and the trigeminal nucleus,29,30 and functionally posterior,31 supra-optic,31 ventromedial,32 and potentially paraventricular31 hypothalamic nuclei are activated by dural nociceptive stimulation. Furthermore, descending hypothalamic projections from the posterior,33,34 lateral, and paraventricular35 hypothalamic nuclei have been shown to control basal and dural evoked nociceptive activation in the TCC. The SuS also receives descending projections from various nuclei of the hypothalamus, as well as limbic and cortical areas.26,36,37 It therefore seems that the SuS is ideally placed to integrate and relay nociceptive and autonomic information to and from the trigeminovascular system as well as being under descending control of the hypothalamus in the pathophysiology of TACs. This anatomy and physiology is summarized in the Figure.
NOVEL ANIMAL MODEL OF TACs In the development of the novel preclinical animal model of TACs presented here, we considered it needed to offer at least 2 of the clinical features of TACs and respond specifically to different therapies that are not effective in other primary headaches. Additionally, to demonstrate the limitation of other animal models and, therefore, the value of a novel approach, and to characterize further the efficacy of this unique animal model, we wanted to compare the treatment effects with an animal model known to reliably explore the pathophysiology of another primary headache disorder. We chose to use dural electrical stimulation as a comparator, as this has been one of the most widely and successfully used in the study of migraine and was familiar to us. In developing this new assay, we chose to combine
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Figure.—Anatomy of trigeminal autonomic cephalalgias (TACs). The trigeminal distribution of pain in TACs is likely to come from activation of the trigeminovascular system, which includes the peripheral afferent projection from the trigeminal ganglion (TG) to the dural vasculature, and the central afferent projection to second-order neurons in the trigeminocervical complex (TCC). Nociceptive incoming signals to the TCC ascend to higher brain structures (light blue neurons) including the midbrain, specific hypothalamic nuclei including the posterior (PH), supra-optic (SON), ventromedial (VMH) and paraventricular hypothalamic nuclei (PVN), as well as thalamocortical neurons. A reflex connection from the TCC (gray neuron), via the superior salivatory nucleus (SuS), provides an autonomic projection to the cranial vasculature. Cranial autonomic features in TACs are thought, in part, to result from activation of this parasympathetic reflex via the outflow from the SuS predominantly through the greater petrosal nerve (green neuron) and its relay with the sphenopalatine ganglion (SPG), but also via the facial (VIIth cranial) nerve (purple neuron). There is hypothalamic activation during TACs, and known descending projections from hypothalamic nuclei to both TCC and SuS nuclei are thought to play an important part in their triggering and the episodic pattern of attacks. Descending projections (red neurons) from PH, PVN, and lateral hypothalamus (LH) are thought to modulate trigeminovascular nociceptive transmission in the TCC. Additionally, it is thought that there is descending control of the TCC through the periaqueductal gray (PAG), locus coeruleus (LC), and nucleus raphe magnus (NRM) projection. Descending projections to the SuS (orange neurons) from LH, PVN, dorsomedial (DMH), and pre-optic hypothalamic nuclei (PON) may control and modulate parasympathetic autonomic projections to the cranial vasculature that result in autonomic symptoms in TACs.
nociceptive trigeminovascular activation with significant activation of the parasympathetic outflow to cranial vasculature to induce severe cranial autonomic symptoms. The link between these 2 systems is the SuS, which is at the heart of the trigeminal autonomic reflex, and also receives important projections from hypothalamic nuclei. It was predicted that activation of the SuS, via electrical stimulation, would produce both trigeminovascular and autonomic symptoms, and it also provides a pathway for the involvement of the hypothalamus in TACs. A summary of the effects of the anti-migraine and anti-TAC drugs in both dural and SuS studies can be found in Table 2.
Vasodilation of Cranial Blood Vessels The craniovascular changes that take place during TACs are now thought to be a response of centrally mediated activation of trigeminovascular and autonomic systems, rather than being potentially the trigger and cause of the pain and other symptoms. To study the role of the vasculature, intravital microscopy was used to measure the changes in dural meningeal blood vessel diameter in response to electrical stimulation of the SuS, using a variety of stimulation parameters. SuS stimulation caused a very modest (3.3 ± 1%) but significant increase in meningeal diameter.14 However, it is known that dural electrical stimulation
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Table 2.—Effect of Primary Headache Treatments in Rodent Models of Migraine and TACs
Triptans Oxygen Hexamethonium CGRP receptor antagonists Naproxen Indomethacin
Dural-evoked vasodilation
Dural-evoked TCC firing
SuS-evoked TCC firing13,14
SuS-evoked lacrimal gland/ duct flow13,14
51-69% inhibition38,42 No effect14 ND 81-98% inhibition38,59 52% inhibition45 30% inhibition44,45
63-70% inhibition56-58 No effect13,14 No effect13 Inhibition60* 17% inhibition13 15% inhibition13
34% inhibition 30% inhibition 25% inhibition 24% inhibition 11% inhibition 30% inhibition
29% inhibition 26% inhibition 36% inhibition No effect No effect 20% inhibition
*There are no data for the effects of CGRP antagonists on dural-evoked responses in rodents; however, it has been shown that olcegepant does significantly inhibit responses in the cat.60 Percentage change is not cited in the article. CGRP = calcitonin gene-related peptide; ND = no data.
causes significant increase in meningeal vessel diameter, mediated predominantly via CGRP release,38 whereas activation of the parasympathetic projection releases VIP to cause cerebral vasodilation.39 Exogenous VIP is much less potent than CGRP at causing vasodilation,40 and this may explain the lack of greater response. Many drugs used in the treatment of migraine that also treat TACs are extremely effective at inhibiting neurogenic dural vasodilation, including triptans,38,41,42 CGRP receptor antagonists,38 topiramate,43 and cyclo-oxygenase (COX) inhibitors, including indomethacin.44,45 However, inhaled oxygen robustly aborts cluster headache,46-48 and there are no robust data for its use in migraine. During these studies, 100% inhaled oxygen was shown to have little effect in neurogenic dural vasodilation.14 This response of a specific cluster headache treatment separates it from the responses of molecules used to treat both migraine and TACs, and provides a first indication that dural stimulation assays of headache may not be ideal to understand the pathophysiology of TACs. Neuronal Responses in the TCC Dural-evoked nociceptive activation of central trigeminovascular neurons and the inhibitory effects of anti-migraine drugs have led to the belief that this is an excellent approach to understand migraine pathophysiology and screen potential anti-migraine drugs. In the novel assay developed for TACs, central trigeminovascular neuronal activity in the TCC was measured in response to SuS stimulation. In preliminary studies, 2 distinct populations of neurons were observed. Those with an extremely short latency of action (between 3 and 20 milliseconds, average 12.1 milliseconds) and those with a much longer latency of action (7-40 milliseconds, average 20.4 milliseconds),13,14 and these neuronal populations seemed to respond differentially to treatments. The shorter latency responses were unaffected by treatment with 15 minutes 100% inhaled oxygen in the rat, whereas the longer latency responses were robustly and reversible inhibited by over 30%.
In order to understand the pathway of activation of both these neuronal populations, their effects were explored further. Hexamethonium bromide is a specific nicotinic autonomic ganglion blocker, which inhibits synaptic transmission and neuronal responses at the level of the autonomic ganglia and does not readily cross the blood-brain barrier.49-51 When this was used against each neuronal population, it had no effect on the shorter latency responses, but significantly inhibited the longer latency response by over 25%. This provides an indication that activation of the parasympathetic outflow to the cranial vasculature (green neurons in the Figure) is necessary for the longer latency responses, although it is not clear at this point whether oxygen works in the same manner or via a different pathway. To dissect this mechanism, both oxygen and hexamethonium were used in the dural nociceptive trigeminovascular model, and it was demonstrated that neither molecule was effective at inhibiting duralevoked firing in the TCC. These data indicate that oxygen, similar to the model of intravital microscopy, has no effect on the trigeminal innervation to the dural vasculature or the central projection to the TCC (black neuron in the Figure). It therefore dissects the locus of action of oxygen to most likely be on the parasympathetic outflow to the cranial vasculature (green neuron in the Figure), and offers, for the first time, a likely neural mode of action in the treatment of cluster headache. The shorter latency response is likely to be a consequence of antidromic activation of the trigeminal autonomic reflex between the TCC and SuS (gray neuron in the Figure). Whether this pathway is also involved in TAC pathophysiology is not known. To further characterize the longer latency neuronal effects, we compared the response of a triptan and CGRP receptor antagonist, known to be effective in dural nociceptive activation models and in the treatment of migraine, with only sumatriptan currently proven to work in cluster headache. The data show that while both were effective at inhibiting SuS-evoked firing, the use of a triptan was significantly more effective than the CGRP receptor antagonist.13 The significant response of both treatments
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might be expected as they are known to act on central trigeminovascular neurons, but the disparity of response with the triptan would seem to indicate that it may be acting on additional sites, most likely the parasympathetic outflow to the cranium, where it is known 5-HT1D receptors are present.52 Finally, the effects of the COX inhibitors indomethacin and naproxen were characterized in both dural and SuS-evoked assays. An indomethacin response defines the diagnosis of paroxysmal hemicrania and hemicrania continua while other COX inhibitors are relatively ineffective,53 whereas naproxen is reliably used in the treatment of migraine.54,55 Both indomethacin and naproxen were equally effective at inhibiting dural-evoked TCC neuronal activity, whereas indomethacin was significantly more effective at inhibiting SuS-evoked neuronal activity than naproxen. These data indicate that a likely action of these COX inhibitors is on central trigeminovascular neurons (black neuron in the Figure), but indomethacin also acts on the parasympathetic outflow to the cranial vasculature (green neuron in the Figure) to exert its effects.
symptoms characteristic of these severe primary headache disorders. It also demonstrates, for the first time, that activation of the cranial parasympathetic pathway is likely to be critical to the development of the trigeminal distribution of pain as well as the cranial autonomic symptoms. Furthermore, these data demonstrate that the locus of action of effective therapeutics for the treatment of these disorders seems to be via this parasympathetic projection, to provide relief of both trigeminovascular and autonomic responses. The development of this assay also opens up opportunities to explore other important issues in the pathophysiology of TACs. These include not only the role that specific hypothalamic nuclei may have in modulating the SuS and its effects on both autonomic and trigeminovascular responses but also the opportunity to screen the efficacy of potentially novel therapeutic targets for the treatment of TACs. This assay may now provide renewed hope to those patients suffering from these terrible disorders that our understanding of these disorders may improve and new medications may be developed to improve their quality of life.
Autonomic Response in the Lacrimal Gland Cranial autonomic symptoms are a significant part of TACs, and so to determine these symptoms in this novel animal model, the change in blood flow around the lacrimal gland/duct was measured in response to SuS stimulation. Using similar stimulation parameters to those used to induce dural vasodilation, SuS stimulation produced characteristic changes in flow in the lacrimal gland/duct that were reproducible many times over 30 minutes.14 Both hexamethonium and oxygen were able to inhibit significantly these reproducible responses maximally by 36% and 26%, respectively. These data are indicative of the fact that autonomic symptoms require activation of the parasympathetic outflow to the cranial vasculature (green neurons in the Figure), across the synapse of the sphenopalatine ganglion, and the ability of oxygen to relieve autonomic symptoms is via this pathway, which is what would have been predicted. Furthermore, treatment with both triptan and indomethacin also inhibited lacrimal flow responses, maximally by 29% and 20%, respectively, whereas both naproxen and the CGRP receptor antagonist were ineffective. Again, these data indicate that both the triptan and indomethacin act, in part, on the parasympathetic outflow to the cranial vasculature to relieve autonomic symptoms of TACs, similar to oxygen, whereas the non-TAC treatments were not effective. Therefore, this novel assay is able to dissect TAC specific treatments that were able to inhibit the SuS-evoked effects on lacrimal flow, while the other headache treatments were ineffective. The data suggest that CGRP receptor antagonists may not be useful in paroxysmal hemicrania and hemicrania continua.
References
CONCLUSION The development of this novel animal model of TACs clearly demonstrates both significant trigeminovascular and autonomic
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HEADACHE CURRENTS
A Novel Translational Animal Model of Trigeminal Autonomic Cephalalgias Simon Akerman, PhD; Peter J. Goadsby, MD, PhD
Overview.—Trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders that involve severe unilateral head pain coupled with significant lateralized cranial autonomic features. Our understanding of these disorders and the development of novel and more effective treatments has been limited by the lack of a suitable animal model to explore their pathophysiology and screen prospective treatments. Discussion.—This review details the development of a novel preclinical model that demonstrates activation of both the trigeminovascular system and parasympathetic projections, thought to be responsible for the severe head pain and autonomic symptoms. Conclusion.—This model demonstrates a unique response to TAC specific treatments and highlights the importance of the cranial parasympathetic pathway to the pathophysiology of TACs and as a potential locus of action for treatments. The development of this model opens up opportunities to understand the pathophysiology of these disorders further, the likely involvement of the hypothalamus, as well as providing a preclinical model with which to screen novel compounds. Key words: trigeminal autonomic cephalalgias, brainstem, superior salivatory nucleus, parasympathetic outflow, triptans, oxygen
Trigeminal autonomic cephalalgias (TACs)1 are highly disabling primary headache disorders characterized by severe unilateral head pain, sometimes described as the worst pain experienced by humans, which occurs in association with ipsilateral cranial autonomic features.2 Their pathophysiology is characterized by 3 major clinical features: unilateral trigeminal distribution of pain, lateralized associated symptoms, including cranial autonomic features,3,4 and an episodic pattern of attacks.5,6 The TACs are differentiated from each other by their highly individual characteristic attack patterns, and also, to some extent, by their response to treatments. Cluster headache attacks tend to have the longest duration with lower attack frequency per day and seem to respond well to oxygen and sumatriptan treatment.7 Paroxysmal hemicrania has an intermediate duration and attack frequency per day and From the Headache Group, Department of Neurology, University of California, San Francisco, CA, USA (S. Akerman); NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, UK (P.J. Goadsby). Address all correspondence to S. Akerman, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Accepted for publication September 10, 2014. ............. Headache © 2015 American Headache Society
is specifically defined by its response to indomethacin.8 Shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) has the shortest duration and has many discrete attacks per day,9 while hemicrania continua has unremitting pain.10 These clinical features and treatments are summarized in Table 1 and reviewed in detail elsewhere.6,11,12 Our basic understanding of the pathophysiology of the TACs is emerging and has come mainly from clinical research and what is observed in clinic. A limitation to furthering our understanding of these severe headache disorders, and particularly in developing novel treatments, has been a lack of reliable, translational animal models. Preclinical animal models of headache have helped us understand the anatomy of the trigeminovascular and cranial autonomic systems, something that is shared in many headache disorders; but they mainly focus on understanding migraine pathophysiology. However, TACs have specific clinical features and response to treatments that separate them from migraine and other headache disorders, and therefore are likely to have a different pathophysiology, and require a specific animal model to understand them more fully. The advantages of a dedicated and specific animal model is that it will allow us to understand further their pathophysiology and, most importantly for the patient, to develop tailored therapies for their treatment. In this review, we describe our recently characterized animal model of TACs and the advantages this now carries in exploring the pathophysiology of TACs and the development of novel treatments.13,14
CLINICAL DATA What is known about TACs and how this may help us in developing an animal model comes partly from the very clear classification of these disorders; the combination of lateralization: of pain, associated features and cranial autonomic features, and some degree of tendency to episodic attacks.5,6 Clinical research reveals that there is activation in the region of the posterior hypothalamic gray matter during the pain in cluster headache,15 paroxysmal hemicrania,16 SUNCT,17,18 and hemicrania continua,19 and deep brain stimulation of this region can relieve cluster headache in some patients.20,21 Also, there is release of calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in cluster headache22 and chronic paroxysmal hemicrania.23 Furthermore, in experimental studies, capsaicin-induced pain in the ophthalmic division of the trigeminal nerve demon............. Conflict of Interest: S.A. none declared. P.J.G. has consulted with manufacturers of medical oxygen Air Products and Linde.
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Table 1.—Clinical Features and Treatments of Trigeminal Autonomic Cephalalgias Cluster Headache
Paroxysmal Hemicrania
SUNCT/SUNA
Sex F : M Pain type Severity Site Attack frequency Duration of attack Autonomic features
1:3 Stabbing, boring Excruciating Orbit, temple 1/alternate days – 8/day 15-180 minutes Yes
1:1 Throbbing, boring, stabbing Excruciating Orbit, temple 1-40/day (>5/day most of the time) 2-30 minutes Yes
Abortive treatments Preventive treatments
Sumatriptan, oxygen Verapamil, lithium
None Indomethacin (absolute response)
1:1.2 Burning, stabbing, sharp Severe to excruciating Periorbital 3-200/day 5-240 seconds Yes (mainly conjunctival injection and lacrimation-SUNCT) None Lamotrigine, topiramate, gabapentin
Table adapted from Cohen et al.11 SUNA = short-lasting unilateral neuralgiform headache; SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
strates many of the vascular changes that are present during TACs, but there is no hypothalamic activation.24 This has led to the hypothesis that the vascular changes taking place in TACs are likely a consequence of activation in the brain, potentially by a dysfunction or activation in the hypothalamus, particularly given the circadian rhythmicity of attacks, which is likely influenced by the suprachiasmatic nucleus. Therefore, in developing an animal model, it is important to consider a centrally mediated mechanism for activation of trigeminovascular and cranial autonomic pathways.
PRECLINICAL DATA To understand what is necessary of an animal model, it is also important to grasp the anatomy and physiology of the pathways involved. The excruciating trigeminal-distribution pain is likely to be a consequence of activation of the trigeminovascular system, including the peripheral afferent projection to the pain-producing cranial vessels of the dura mater and the central projection to the trigeminal nucleus caudalis and its extension to the cervical spinal cord, the trigeminocervical complex (TCC). Nociceptive activation of this pathway in animals has been shown to cause neuronal activation in the superior salivatory nucleus (SuS) within the pons,25 through the trigeminal autonomic reflex arc, and is the origin of cells for the cranial parasympathetic autonomic vasodilator pathway.26 This efferent projection is predominantly through the greater petrosal nerve, a branch of the facial (VIIth) cranial nerve, and its projection through the sphenopalatine (sometimes called pterygopalatine) ganglion.27 Autonomic symptoms in migraine are believed to result from activation of the trigeminal autonomic reflex arc to the SuS and its projection to the cranial vessels and lacrimal glands. A significant and defining feature in TACs is their lateralized cranial autonomic features, which include lacrimation, conjunctival injection, aural fullness, and nasal congestion and a local third-order sympathetic lesion
due to carotid swelling.28 Therefore, activation of this projection from the SuS is thought to play a far more significant role in TAC pathophysiology. The hypothalamus, as suggested by imaging studies during TACs, is clearly an important region in their pathophysiology. Anatomically, there are reciprocal connections between various nuclei of the hypothalamus and the trigeminal nucleus,29,30 and functionally posterior,31 supra-optic,31 ventromedial,32 and potentially paraventricular31 hypothalamic nuclei are activated by dural nociceptive stimulation. Furthermore, descending hypothalamic projections from the posterior,33,34 lateral, and paraventricular35 hypothalamic nuclei have been shown to control basal and dural evoked nociceptive activation in the TCC. The SuS also receives descending projections from various nuclei of the hypothalamus, as well as limbic and cortical areas.26,36,37 It therefore seems that the SuS is ideally placed to integrate and relay nociceptive and autonomic information to and from the trigeminovascular system as well as being under descending control of the hypothalamus in the pathophysiology of TACs. This anatomy and physiology is summarized in the Figure.
NOVEL ANIMAL MODEL OF TACs In the development of the novel preclinical animal model of TACs presented here, we considered it needed to offer at least 2 of the clinical features of TACs and respond specifically to different therapies that are not effective in other primary headaches. Additionally, to demonstrate the limitation of other animal models and, therefore, the value of a novel approach, and to characterize further the efficacy of this unique animal model, we wanted to compare the treatment effects with an animal model known to reliably explore the pathophysiology of another primary headache disorder. We chose to use dural electrical stimulation as a comparator, as this has been one of the most widely and successfully used in the study of migraine and was familiar to us. In developing this new assay, we chose to combine
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Figure.—Anatomy of trigeminal autonomic cephalalgias (TACs). The trigeminal distribution of pain in TACs is likely to come from activation of the trigeminovascular system, which includes the peripheral afferent projection from the trigeminal ganglion (TG) to the dural vasculature, and the central afferent projection to second-order neurons in the trigeminocervical complex (TCC). Nociceptive incoming signals to the TCC ascend to higher brain structures (light blue neurons) including the midbrain, specific hypothalamic nuclei including the posterior (PH), supra-optic (SON), ventromedial (VMH) and paraventricular hypothalamic nuclei (PVN), as well as thalamocortical neurons. A reflex connection from the TCC (gray neuron), via the superior salivatory nucleus (SuS), provides an autonomic projection to the cranial vasculature. Cranial autonomic features in TACs are thought, in part, to result from activation of this parasympathetic reflex via the outflow from the SuS predominantly through the greater petrosal nerve (green neuron) and its relay with the sphenopalatine ganglion (SPG), but also via the facial (VIIth cranial) nerve (purple neuron). There is hypothalamic activation during TACs, and known descending projections from hypothalamic nuclei to both TCC and SuS nuclei are thought to play an important part in their triggering and the episodic pattern of attacks. Descending projections (red neurons) from PH, PVN, and lateral hypothalamus (LH) are thought to modulate trigeminovascular nociceptive transmission in the TCC. Additionally, it is thought that there is descending control of the TCC through the periaqueductal gray (PAG), locus coeruleus (LC), and nucleus raphe magnus (NRM) projection. Descending projections to the SuS (orange neurons) from LH, PVN, dorsomedial (DMH), and pre-optic hypothalamic nuclei (PON) may control and modulate parasympathetic autonomic projections to the cranial vasculature that result in autonomic symptoms in TACs.
nociceptive trigeminovascular activation with significant activation of the parasympathetic outflow to cranial vasculature to induce severe cranial autonomic symptoms. The link between these 2 systems is the SuS, which is at the heart of the trigeminal autonomic reflex, and also receives important projections from hypothalamic nuclei. It was predicted that activation of the SuS, via electrical stimulation, would produce both trigeminovascular and autonomic symptoms, and it also provides a pathway for the involvement of the hypothalamus in TACs. A summary of the effects of the anti-migraine and anti-TAC drugs in both dural and SuS studies can be found in Table 2.
Vasodilation of Cranial Blood Vessels The craniovascular changes that take place during TACs are now thought to be a response of centrally mediated activation of trigeminovascular and autonomic systems, rather than being potentially the trigger and cause of the pain and other symptoms. To study the role of the vasculature, intravital microscopy was used to measure the changes in dural meningeal blood vessel diameter in response to electrical stimulation of the SuS, using a variety of stimulation parameters. SuS stimulation caused a very modest (3.3 ± 1%) but significant increase in meningeal diameter.14 However, it is known that dural electrical stimulation
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Table 2.—Effect of Primary Headache Treatments in Rodent Models of Migraine and TACs
Triptans Oxygen Hexamethonium CGRP receptor antagonists Naproxen Indomethacin
Dural-evoked vasodilation
Dural-evoked TCC firing
SuS-evoked TCC firing13,14
SuS-evoked lacrimal gland/ duct flow13,14
51-69% inhibition38,42 No effect14 ND 81-98% inhibition38,59 52% inhibition45 30% inhibition44,45
63-70% inhibition56-58 No effect13,14 No effect13 Inhibition60* 17% inhibition13 15% inhibition13
34% inhibition 30% inhibition 25% inhibition 24% inhibition 11% inhibition 30% inhibition
29% inhibition 26% inhibition 36% inhibition No effect No effect 20% inhibition
*There are no data for the effects of CGRP antagonists on dural-evoked responses in rodents; however, it has been shown that olcegepant does significantly inhibit responses in the cat.60 Percentage change is not cited in the article. CGRP = calcitonin gene-related peptide; ND = no data.
causes significant increase in meningeal vessel diameter, mediated predominantly via CGRP release,38 whereas activation of the parasympathetic projection releases VIP to cause cerebral vasodilation.39 Exogenous VIP is much less potent than CGRP at causing vasodilation,40 and this may explain the lack of greater response. Many drugs used in the treatment of migraine that also treat TACs are extremely effective at inhibiting neurogenic dural vasodilation, including triptans,38,41,42 CGRP receptor antagonists,38 topiramate,43 and cyclo-oxygenase (COX) inhibitors, including indomethacin.44,45 However, inhaled oxygen robustly aborts cluster headache,46-48 and there are no robust data for its use in migraine. During these studies, 100% inhaled oxygen was shown to have little effect in neurogenic dural vasodilation.14 This response of a specific cluster headache treatment separates it from the responses of molecules used to treat both migraine and TACs, and provides a first indication that dural stimulation assays of headache may not be ideal to understand the pathophysiology of TACs. Neuronal Responses in the TCC Dural-evoked nociceptive activation of central trigeminovascular neurons and the inhibitory effects of anti-migraine drugs have led to the belief that this is an excellent approach to understand migraine pathophysiology and screen potential anti-migraine drugs. In the novel assay developed for TACs, central trigeminovascular neuronal activity in the TCC was measured in response to SuS stimulation. In preliminary studies, 2 distinct populations of neurons were observed. Those with an extremely short latency of action (between 3 and 20 milliseconds, average 12.1 milliseconds) and those with a much longer latency of action (7-40 milliseconds, average 20.4 milliseconds),13,14 and these neuronal populations seemed to respond differentially to treatments. The shorter latency responses were unaffected by treatment with 15 minutes 100% inhaled oxygen in the rat, whereas the longer latency responses were robustly and reversible inhibited by over 30%.
In order to understand the pathway of activation of both these neuronal populations, their effects were explored further. Hexamethonium bromide is a specific nicotinic autonomic ganglion blocker, which inhibits synaptic transmission and neuronal responses at the level of the autonomic ganglia and does not readily cross the blood-brain barrier.49-51 When this was used against each neuronal population, it had no effect on the shorter latency responses, but significantly inhibited the longer latency response by over 25%. This provides an indication that activation of the parasympathetic outflow to the cranial vasculature (green neurons in the Figure) is necessary for the longer latency responses, although it is not clear at this point whether oxygen works in the same manner or via a different pathway. To dissect this mechanism, both oxygen and hexamethonium were used in the dural nociceptive trigeminovascular model, and it was demonstrated that neither molecule was effective at inhibiting duralevoked firing in the TCC. These data indicate that oxygen, similar to the model of intravital microscopy, has no effect on the trigeminal innervation to the dural vasculature or the central projection to the TCC (black neuron in the Figure). It therefore dissects the locus of action of oxygen to most likely be on the parasympathetic outflow to the cranial vasculature (green neuron in the Figure), and offers, for the first time, a likely neural mode of action in the treatment of cluster headache. The shorter latency response is likely to be a consequence of antidromic activation of the trigeminal autonomic reflex between the TCC and SuS (gray neuron in the Figure). Whether this pathway is also involved in TAC pathophysiology is not known. To further characterize the longer latency neuronal effects, we compared the response of a triptan and CGRP receptor antagonist, known to be effective in dural nociceptive activation models and in the treatment of migraine, with only sumatriptan currently proven to work in cluster headache. The data show that while both were effective at inhibiting SuS-evoked firing, the use of a triptan was significantly more effective than the CGRP receptor antagonist.13 The significant response of both treatments
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might be expected as they are known to act on central trigeminovascular neurons, but the disparity of response with the triptan would seem to indicate that it may be acting on additional sites, most likely the parasympathetic outflow to the cranium, where it is known 5-HT1D receptors are present.52 Finally, the effects of the COX inhibitors indomethacin and naproxen were characterized in both dural and SuS-evoked assays. An indomethacin response defines the diagnosis of paroxysmal hemicrania and hemicrania continua while other COX inhibitors are relatively ineffective,53 whereas naproxen is reliably used in the treatment of migraine.54,55 Both indomethacin and naproxen were equally effective at inhibiting dural-evoked TCC neuronal activity, whereas indomethacin was significantly more effective at inhibiting SuS-evoked neuronal activity than naproxen. These data indicate that a likely action of these COX inhibitors is on central trigeminovascular neurons (black neuron in the Figure), but indomethacin also acts on the parasympathetic outflow to the cranial vasculature (green neuron in the Figure) to exert its effects.
symptoms characteristic of these severe primary headache disorders. It also demonstrates, for the first time, that activation of the cranial parasympathetic pathway is likely to be critical to the development of the trigeminal distribution of pain as well as the cranial autonomic symptoms. Furthermore, these data demonstrate that the locus of action of effective therapeutics for the treatment of these disorders seems to be via this parasympathetic projection, to provide relief of both trigeminovascular and autonomic responses. The development of this assay also opens up opportunities to explore other important issues in the pathophysiology of TACs. These include not only the role that specific hypothalamic nuclei may have in modulating the SuS and its effects on both autonomic and trigeminovascular responses but also the opportunity to screen the efficacy of potentially novel therapeutic targets for the treatment of TACs. This assay may now provide renewed hope to those patients suffering from these terrible disorders that our understanding of these disorders may improve and new medications may be developed to improve their quality of life.
Autonomic Response in the Lacrimal Gland Cranial autonomic symptoms are a significant part of TACs, and so to determine these symptoms in this novel animal model, the change in blood flow around the lacrimal gland/duct was measured in response to SuS stimulation. Using similar stimulation parameters to those used to induce dural vasodilation, SuS stimulation produced characteristic changes in flow in the lacrimal gland/duct that were reproducible many times over 30 minutes.14 Both hexamethonium and oxygen were able to inhibit significantly these reproducible responses maximally by 36% and 26%, respectively. These data are indicative of the fact that autonomic symptoms require activation of the parasympathetic outflow to the cranial vasculature (green neurons in the Figure), across the synapse of the sphenopalatine ganglion, and the ability of oxygen to relieve autonomic symptoms is via this pathway, which is what would have been predicted. Furthermore, treatment with both triptan and indomethacin also inhibited lacrimal flow responses, maximally by 29% and 20%, respectively, whereas both naproxen and the CGRP receptor antagonist were ineffective. Again, these data indicate that both the triptan and indomethacin act, in part, on the parasympathetic outflow to the cranial vasculature to relieve autonomic symptoms of TACs, similar to oxygen, whereas the non-TAC treatments were not effective. Therefore, this novel assay is able to dissect TAC specific treatments that were able to inhibit the SuS-evoked effects on lacrimal flow, while the other headache treatments were ineffective. The data suggest that CGRP receptor antagonists may not be useful in paroxysmal hemicrania and hemicrania continua.
References
CONCLUSION The development of this novel animal model of TACs clearly demonstrates both significant trigeminovascular and autonomic
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