RESUMEN
Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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Encéfalo/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Cognición/fisiología , Trastornos Migrañosos/fisiopatología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Animales , Humanos , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/metabolismo , Receptores de Serotonina/metabolismo , Receptor de Serotonina 5-HT1FRESUMEN
PURPOSE OF REVIEW: To provide an overview and highlight recent updates in temporomandibular disorders (TMDs) and their comorbidity with headache disorders regarding pathophysiology and management. RECENT FINDINGS: In the last decade, there have been great advancements in the understanding of TMDs and their relationship with neurovascular pains such as headaches. Understanding of TMDs is necessary for the context of its comorbidity with primary headache disorders. The literature regarding management of these comorbidities is scarce but points to combination therapy including pharmacological and non-pharmacological approaches to optimize management. The use of CGRP receptor-targeted monoclonal antibodies or CGRP receptor antagonists should be explored for the management of chronic TMDs. It could also be used as a novel monotherapy or in combination with non-pharmacological approaches for TMDs' comorbidity with headache, particularly migraine. Research is needed to support evidence-based management protocols. A team involving neurology (headache medicine) and dentistry (orofacial pain) is critical for optimal management.
RESUMEN
BACKGROUND: Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. METHODS: Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. RESULTS: Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. CONCLUSION: Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.
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Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratas , Animales , Masculino , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Ratas Sprague-Dawley , Área Tegmental Ventral , Glucemia , Quinpirol/farmacología , Neuronas , PercepciónRESUMEN
BACKGROUND: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. METHODS: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. RESULTS: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. CONCLUSION: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.
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Depresión de Propagación Cortical , Receptores Opioides , Receptores de Serotonina 5-HT1 , Animales , Ratas , Neuronas , Nociceptores , Receptores Opioides/fisiología , Receptores de Serotonina 5-HT1/fisiologíaRESUMEN
PURPOSE OF REVIEW: Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15 years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine. RECENT FINDINGS: Non-invasive vagus nerve stimulation and spring-pulse transcranial magnetic stimulation are both cleared for the treatment of migraine, supported by preclinical studies that validate efficacy and mechanism of action, and complemented with clinical trial data. Other options also authorized for use include transcutaneous supraorbital nerve stimulation and remote electrical neuromodulation. Various options are available to treat migraine using authorized neuromodulatory devices. These data support their efficacy in the treatment of episodic migraine, although further studies are necessary to elucidate their mechanism of action and to provide rigor to clinical trial data.
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Trastornos Migrañosos , Estimulación Eléctrica Transcutánea del Nervio , Estimulación del Nervio Vago , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Reactive nitroxidative species, such as nitric oxide but particularly peroxynitrite, have been strongly implicated in pain mechanisms. Targeting peroxynitrite is anti-nociceptive in pain models, but little is known about its role in migraine mechanisms. Given the need to validate novel targets for migraine headache, our objective was to study the potential of reactive nitroxidative species, particularly peroxynitrite, as novel targets for drug discovery and their role in migraine mechanisms. METHODS: We recorded neuronal activity in rats with extracellular electrodes and examined the effects of targeting nitric oxide or peroxynitrite on ongoing and cranial-evoked firing rates of central trigeminocervical neurons. We injected calcitonin gene-related peptide (which produces migraine-like headache in migraineurs) and characterized neuronal responses to cranial stimulation and on behavioral responses to nociceptive periorbital stimulation and determined the effects of targeting reactive nitroxidative species on the mediated changes. RESULTS: L-NAME (nitric oxide synthase inhibitor) and Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride (FeTPPS; peroxynitrite decomposition catalyst) inhibited ongoing and dural-evoked responses of trigeminocervical neurons, without affecting normal facial-cutaneous responses. Calcitonin gene-related peptide caused activation and sensitization of dural-responsive trigeminovascular neurons with hypersensitivity to intracranial and extracranial stimulation, and reduction of periorbital withdrawal thresholds. Only the peroxynitrite decomposition catalyst prevented these neuronal and behavioral nociceptive responses. DISCUSSION: The data support that calcitonin gene-related peptide mediates the underlying neurobiological mechanisms related to the development of migraine-like headache. They also confirm the role of nitric oxide and implicate peroxynitrite production along the trigeminovascular migraine pathway in these mechanisms. The data also support peroxynitrite as a novel and potentially effective target for migraine treatment. The current drug development focus on peroxynitrite decomposition catalysts for chronic pain disorders should therefore extend to migraine.
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Trastornos Migrañosos , Animales , Péptido Relacionado con Gen de Calcitonina , Cefalea , Trastornos Migrañosos/tratamiento farmacológico , Neuronas , Óxido Nítrico , RatasRESUMEN
Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia-neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.
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Dolor Facial/metabolismo , Dolor Facial/fisiopatología , Neuroglía/fisiología , Animales , Dolor Facial/terapia , Neoplasias de Cabeza y Cuello/fisiopatología , Cefalea/fisiopatología , Humanos , Inflamación/fisiopatología , Microglía/fisiología , Neuronas/fisiología , Nocicepción/fisiología , Ganglio del Trigémino/fisiologíaRESUMEN
Cranial allodynia associated with spontaneous migraine is reported as either responsive to triptan treatment or to be predictive of lack of triptan efficacy. These conflicting results suggest that a single mechanism mediating the underlying neurophysiology of migraine symptoms is unlikely. The lack of a translational approach to study cranial allodynia reported in migraine patients is a limitation in dissecting potential mechanisms. Our objective was to study triptan-responsive cranial allodynia in migraine patients, and to develop an approach to studying its neural basis in the laboratory. Using nitroglycerine to trigger migraine attacks, we investigated whether cranial allodynia could be triggered experimentally, observing its response to treatment. Preclinically, we examined the cephalic response properties of central trigeminocervical neurons using extracellular recording techniques, determining changes to ongoing firing and somatosensory cranial-evoked sensitivity, in response to nitroglycerine followed by triptan treatment. Cranial allodynia was triggered alongside migraine-like headache in nearly half of subjects. Those who reported cranial allodynia accompanying their spontaneous migraine attacks were significantly more likely to have symptoms triggered than those that did not. Patients responded to treatment with aspirin or sumatriptan. Preclinically, nitroglycerine caused an increase in ongoing firing and hypersensitivity to intracranial-dural and extracranial-cutaneous (noxious and innocuous) somatosensory stimulation, reflecting signatures of central sensitization potentially mediating throbbing headache and cranial allodynia. These responses were aborted by a triptan. These data suggest that nitroglycerine can be used as an effective and reliable method to trigger cranial allodynia in subjects during evoked migraine, and the symptom is responsive to abortive triptan treatments. Preclinically, nitroglycerine activates the underlying neural mechanism of cephalic migraine symptoms, central sensitization, also predicting the clinical outcome to triptans. This supports a biological rationale that several mechanisms can mediate the underlying neurophysiology of migraine symptoms, with nitrergic-induced changes reflecting one that is relevant to spontaneous migraine in many migraineurs, whose symptoms of cranial allodynia are responsive to triptan treatment. This approach translates directly to responses in animals and is therefore a relevant platform to study migraine pathophysiology, and for use in migraine drug discovery.
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Hiperalgesia/fisiopatología , Trastornos Migrañosos/fisiopatología , Nervio Trigémino/fisiología , Adolescente , Adulto , Aspirina/uso terapéutico , Método Doble Ciego , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Persona de Mediana Edad , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/tratamiento farmacológico , Nitroglicerina , Nervios Espinales/fisiología , Sumatriptán/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: To review and discuss the literature relevant to the role of brainstem structure and function in headache. BACKGROUND: Primary headache disorders, such as migraine and cluster headache, are considered disorders of the brain. As well as head-related pain, these headache disorders are also associated with other neurological symptoms, such as those related to sensory, homeostatic, autonomic, cognitive and affective processing that can all occur before, during or even after headache has ceased. Many imaging studies demonstrate activation in brainstem areas that appear specifically associated with headache disorders, especially migraine, which may be related to the mechanisms of many of these symptoms. This is further supported by preclinical studies, which demonstrate that modulation of specific brainstem nuclei alters sensory processing relevant to these symptoms, including headache, cranial autonomic responses and homeostatic mechanisms. REVIEW FOCUS: This review will specifically focus on the role of brainstem structures relevant to primary headaches, including medullary, pontine, and midbrain, and describe their functional role and how they relate to mechanisms of primary headaches, especially migraine.
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Tronco Encefálico/fisiopatología , Cefalea/fisiopatología , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Barrera Hematoencefálica , Cefalalgia Histamínica/fisiopatología , Cefalea/tratamiento farmacológico , Cefaleas Primarias/fisiopatología , Homeostasis , Humanos , Trastornos Migrañosos/fisiopatología , Vías Nerviosas/fisiopatología , Sistema Nervioso Parasimpático/fisiopatología , Estimulación Física/efectos adversos , Nervio Trigémino/fisiopatología , Núcleos del Trigémino/fisiopatología , Nervio Vago/fisiopatología , VasodilataciónRESUMEN
Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.
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Medicina Tradicional China/métodos , Trastornos Migrañosos , Neuronas Aferentes/efectos de los fármacos , Manejo del Dolor/métodos , Nervio Trigémino/efectos de los fármacos , Animales , Alcoholes Bencílicos/farmacología , Modelos Animales de Enfermedad , Duramadre , Glucósidos/farmacología , Levetiracetam/farmacología , Masculino , Dolor Nociceptivo , Propranolol/farmacología , Pirazinas/farmacología , Ratas Sprague-DawleyRESUMEN
The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research. In addition to suggesting potential therapeutic targets for migraine, the finding provides an opportunity to better understand the pathological events from early events (aura) to the headache itself. Although PACAP-38 and the closely related peptide VIP (vasoactive intestinal peptide) are well-known as vasoactive molecules, the dilation of cranial blood vessels per se is no longer felt to underlie migraine headaches. Thus, more recent research has focused on other possible PACAP-mediated mechanisms, and has raised some important questions. For example, (1) are endogenous sources of PACAP (or VIP) involved in the triggering and/or propagation of migraine headaches?; (2) which receptor subtypes are involved in migraine pathophysiology?; (3) can we identify specific anatomical circuit(s) where PACAP signaling is involved in the features of migraine? The purpose of this review is to discuss the possibility, and supportive evidence, that PACAP acts to induce migraine-like symptoms not only by directly modulating nociceptive neural circuits, but also by indirectly regulating the production of inflammatory mediators. We focus here primarily on postulated extra-dural sites because potential mechanisms of PACAP action in the dura are discussed in detail elsewhere (see X, this edition).
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Mediadores de Inflamación/metabolismo , Trastornos Migrañosos/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , HumanosRESUMEN
Vagus nerve stimulation (VNS) has been reported to be effective in the abortive treatment of both migraine and cluster headache. Using validated animal models of acute dural-intracranial (migraine-like) and trigeminal-autonomic (cluster-like) head pain we tested whether VNS suppresses ongoing and nociceptive-evoked firing of trigeminocervical neurons to explain its abortive effects in migraine and cluster headache. Unilateral VNS was applied invasively via hook electrodes placed on the vagus nerve. A single dose of ipsilateral or contralateral VNS, to trigeminal recording and dural-stimulating side, suppressed ongoing spontaneous and noxious dural-evoked trigeminocervical neuronal firing. This effect was dose-dependent, with two doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing (maximally by ~60%) for up to three hours, and dural-evoked (Aδ-fiber; by ~22%, C-fiber: by ~55%) responses for at least two hours. Statistically, there was no difference between ipsilateral and contralateral groups. Two doses of VNS also suppressed superior salivatory nucleus-evoked trigeminocervical neuronal responses (maximally by ~22%) for 2.5h, to model nociceptive activation of the trigeminal-autonomic pathway. VNS had no effect on normal somatosensory cutaneous facial responses throughout. These studies provide a mechanistic rationale for the observed benefits of VNS in the abortive treatment of migraine and cluster headache. In addition, they further validate these preclinical models as suitable approaches to optimize therapeutic efficacy, and provide an opportunity to hypothesize and dissect the neurobiological mechanisms of VNS in the treatment of primary headaches.
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Cefalea/fisiopatología , Cefalea/terapia , Neuronas/fisiología , Núcleos del Trigémino/fisiopatología , Estimulación del Nervio Vago , Potenciales de Acción , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Duramadre/fisiopatología , Electrodos Implantados , Lateralidad Funcional/fisiología , Masculino , Dolor Nociceptivo/fisiopatología , Dolor Nociceptivo/terapia , Distribución Aleatoria , Ratas Sprague-Dawley , Estimulación del Nervio Vago/métodosRESUMEN
Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10U·kg-1), glucagon (100µg·200µl-1) and leptin (0.3, 1 and 3mg·kg-1) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p<0.001) and leptin (p<0.01) whereas glucagon had the opposite effect (p<0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p<0.001), glucagon (p<0.05) and leptin (p<0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p<0.001), and increased by glucagon (p<0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p<0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction.
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Glucagón/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Trastornos Migrañosos/metabolismo , Neuronas/metabolismo , Núcleos del Trigémino/metabolismo , Analgésicos no Narcóticos/administración & dosificación , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Glucagón/administración & dosificación , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/patología , Insulina/administración & dosificación , Leptina/administración & dosificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Trastornos Migrañosos/patología , Trastornos Migrañosos/prevención & control , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Dolor/metabolismo , Dolor/patología , Dolor/prevención & control , Ratas Sprague-Dawley , Núcleos del Trigémino/patologíaRESUMEN
A single pulse of transcranial magnetic stimulation has been shown to be effective for the acute treatment of migraine with and without aura. Here we aimed to investigate the potential mechanisms of action of transcranial magnetic stimulation, using a transcortical approach, in preclinical migraine models. We tested the susceptibility of cortical spreading depression, the experimental correlate of migraine aura, and further evaluated the response of spontaneous and evoked trigeminovascular activity of second order trigemontothalamic and third order thalamocortical neurons in rats. Single pulse transcranial magnetic stimulation significantly inhibited both mechanical and chemically-induced cortical spreading depression when administered immediately post-induction in rats, but not when administered preinduction, and when controlled by a sham stimulation. Additionally transcranial magnetic stimulation significantly inhibited the spontaneous and evoked firing rate of third order thalamocortical projection neurons, but not second order neurons in the trigeminocervical complex, suggesting a potential modulatory effect that may underlie its utility in migraine. In gyrencephalic cat cortices, when administered post-cortical spreading depression, transcranial magnetic stimulation blocked the propagation of cortical spreading depression in two of eight animals. These results are the first to demonstrate that cortical spreading depression can be blocked in vivo using single pulse transcranial magnetic stimulation and further highlight a novel thalamocortical modulatory capacity that may explain the efficacy of magnetic stimulation in the treatment of migraine with and without aura.
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Depresión de Propagación Cortical/fisiología , Migraña con Aura/terapia , Neuronas/fisiología , Tálamo/fisiopatología , Estimulación Magnética Transcraneal/métodos , Nervio Trigémino/fisiopatología , Animales , Gatos , Modelos Animales de Enfermedad , Estimulación Eléctrica , Electroencefalografía , Flujometría por Láser-Doppler , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Migraine is a common and complex brain disorder. Although it is clear that head pain is a key manifestation of the disorder for most patients, what drives the activation of neuronal pain pathways in susceptible patients is less obvious. There is growing evidence that migraine pathophysiology may, in part, include dysfunction of subcortical structures. These include diencephalic and brainstem nuclei that can modulate the perception of activation of the trigeminovascular system, which carries sensory information from the cranial vasculature to the brain. Dysfunction of these nuclei, and their connections to other key brain centres, may contribute to the cascade of events that results in other symptoms of migraine - such as light and sound sensitivity - thus providing a comprehensive explanation of the neurobiology of the disorder.
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Tronco Encefálico/fisiopatología , Diencéfalo/fisiopatología , Trastornos Migrañosos/fisiopatología , Humanos , Vías Nerviosas/fisiopatologíaRESUMEN
OBJECTIVE: To examine the effect of the orexinergic blockade with a dual orexin receptor antagonist (DORA) on experimental models of peripheral and central trigeminal as well as cortical activation relevant to migraine and migraine aura. METHODS: In this study we used a precursor of suvorexant, a dual orexin receptor antagonist #12 (DORA-12) in established experimental in vivo models of dural trigeminovascular nociception in rat. Neurogenic dural vasodilation and electrophysiological recordings of second order trigeminocervical neurons were used to study trigeminal nociceptive mechanisms directly. KCl-evoked cortical spreading depression was also used as a surrogate for migraine aura. RESULTS: Neurogenically-induced vasodilation of the middle meningeal artery, caused by nociceptive activation of peripheral afferent projections of the trigeminal nerve, was attenuated by intravenous DORA-12 (1 mgkg(-1)). Second-order trigeminocervical complex neuronal activity was significantly inhibited by intravenous DORA-12 (1 mgkg(-1)). DORA-12 significantly reduced susceptibility to KCl-evoked cortical spreading depression. CONCLUSION: The study provides the first direct evidence, that simultaneous antagonism on both orexin receptors is able to attenuate trigeminal nociceptive activity as well as to induce an elevation of the threshold for the induction of a cortical spreading depression (CSD). In the clinical context, these data imply that targeting the hypothalamic orexinergic system may offer an entirely novel mechanism for the preventive treatment of migraine with and without aura.
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Azepinas/farmacología , Bencimidazoles/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Animales , Azepinas/química , Bencimidazoles/química , Fármacos del Sistema Nervioso Central/farmacología , Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Masculino , Microelectrodos , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Antagonistas de los Receptores de Orexina/química , Cloruro de Potasio/farmacología , Ratas Sprague-Dawley , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
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.
Asunto(s)
Analgésicos/uso terapéutico , Evaluación Preclínica de Medicamentos , Cefalalgia Autónoma del Trigémino/terapia , Animales , Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica , Femenino , Humanos , Masculino , Cefalalgia Autónoma del Trigémino/diagnósticoRESUMEN
Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine. Endocannabinoids, as well as being physiologically analgesic, are known to inhibit dural trigeminovascular nociceptive responses. They are also involved in the descending modulation of cutaneous-evoked C-fiber spinal nociceptive responses from the brainstem. The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and/or cutaneous facial trigeminovascular nociceptive responses, from the brainstem ventrolateral periaqueductal gray (vlPAG). CB1 receptor activation in the vlPAG attenuated dural-evoked Aδ-fiber neurons (maximally by 19%) and basal spontaneous activity (maximally by 33%) in the rat trigeminocervical complex, but there was no effect on cutaneous facial receptive field responses. This inhibitory vlPAG-mediated modulation was inhibited by specific CB1 receptor antagonism, given via the vlPAG, and with a 5-HT1B/1D receptor antagonist, given either locally in the vlPAG or systemically. These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ-fiber dural-nociceptive responses, which differs from the way the brainstem modulates spinal nociceptive transmission. Furthermore, our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information, suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG.
Asunto(s)
Endocannabinoides/metabolismo , Dolor/fisiopatología , Sustancia Gris Periacueductal/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptores de Serotonina/metabolismo , Animales , Ácidos Araquidónicos/farmacología , Bicuculina/administración & dosificación , Agonistas de Receptores de Cannabinoides/farmacología , Modelos Animales de Enfermedad , Endocannabinoides/farmacología , Antagonistas de Receptores de GABA-A/administración & dosificación , Masculino , Microinyecciones , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/fisiología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Serotoninérgicos/farmacología , Antagonistas de la Serotonina/farmacología , Piel/inervación , Núcleos del TrigéminoRESUMEN
Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.
Asunto(s)
Canales de Calcio/metabolismo , Neuronas/metabolismo , Nocicepción/fisiología , Seno Sagital Superior/metabolismo , Núcleos Talámicos/metabolismo , Núcleos del Trigémino/metabolismo , Animales , Canales de Calcio/genética , Ataxia Cerebelosa/genética , Estimulación Eléctrica , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastornos Migrañosos/genética , Mutación Missense , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Nocicepción/efectos de los fármacos , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Seno Sagital Superior/efectos de los fármacos , Núcleos Talámicos/efectos de los fármacos , Núcleo Caudal del Trigémino/efectos de los fármacos , Núcleo Caudal del Trigémino/metabolismo , Núcleos del Trigémino/efectos de los fármacos , Triptaminas/farmacologíaRESUMEN
Migraine is a severe and debilitating disorder of the brain that involves a constellation of neurological symptoms alongside head pain. Its pathophysiology is only beginning to be understood, and is thought to involve activation and sensitization of trigeminovascular nociceptive pathways that innervate the cranial vasculature, and activation of brain stem nuclei. Much of our understanding of migraine pathophysiology stems from research conducted in animal models over the last 30 years, and the development of unique assays in animals that try to model specific aspects of migraine pathophysiology related to particular symptoms. This review will highlight some of the latest findings from these established animal models, as well as discuss the latest in the development of novel approaches in animals to study migraine.