RESUMEN
Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10â pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.
Asunto(s)
Trastornos Migrañosos , Cefalea Postraumática , Adulto , Humanos , Femenino , Masculino , Cefalea Postraumática/tratamiento farmacológico , Cefalea Postraumática/diagnóstico , Cefalea Postraumática/etiología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/uso terapéutico , Cefalea/etiología , Cefalea/complicaciones , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/complicaciones , Método Doble CiegoRESUMEN
Recently, we showed that while atogepant-a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist-does not fully prevent activation of meningeal nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C fibres and late response probability in Aδ fibres. The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons. In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 versus 1/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 versus 5/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant's inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant' ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated Aδ fibres. Atogepant's inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Depresión de Propagación Cortical , Trastornos Migrañosos , Ratas Sprague-Dawley , Animales , Masculino , Trastornos Migrañosos/prevención & control , Trastornos Migrañosos/tratamiento farmacológico , Ratas , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Núcleo Espinal del Trigémino/efectos de los fármacos , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiologíaRESUMEN
BACKGROUND: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140â mg erenumab on day 1. They were then randomized to receive sildenafil 100â mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. RESULTS: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12â h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p < 0.001) during the first hour after administration compared to placebo. CONCLUSION: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT05889455.
Asunto(s)
Estudios Cruzados , GMP Cíclico , Trastornos Migrañosos , Receptores de Péptido Relacionado con el Gen de Calcitonina , Citrato de Sildenafil , Humanos , Adulto , Masculino , Método Doble Ciego , Femenino , Citrato de Sildenafil/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/inducido químicamente , Persona de Mediana Edad , GMP Cíclico/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Inhibidores de Fosfodiesterasa 5/farmacología , Adulto JovenRESUMEN
BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.
Asunto(s)
Canales KATP , Trastornos Migrañosos , Adulto , Humanos , Receptores de Péptido Relacionado con el Gen de Calcitonina , Cromakalim , Estudios Cruzados , Trastornos Migrañosos/inducido químicamente , Anticuerpos Monoclonales , Adenosina TrifosfatoRESUMEN
Spreading depolarization (SD), the underlying mechanism of migraine aura, may trigger the opening of the pannexin 1 (PANX1) pore to sustain the cortical neuroinflammatory cascades involved in the genesis of headache. Yet, the mechanism underlying SD-evoked neuroinflammation and trigeminovascular activation remains incompletely understood. We characterized the identity of inflammasome activated following SD-evoked PANX1 opening. Pharmacological inhibitors targeting PANX1 or NLRP3 as well as genetic ablation of Nlrp3 and Il1b were applied to investigate the molecular mechanism of the downstream neuroinflammatory cascades. In addition, we examined whether SD-triggered microglial activation facilitates neuronal NLRP3-mediated inflammatory cascades. Pharmacological inhibition of toll-like receptors TLR2/4, the potential receptors of the damage-associated molecular pattern HMGB1, was further employed to interrogate the neuron-microglia interplay in SD-induced neuroinflammation. We found that NLRP3 but not NLRP1 or NLRP2 inflammasome was activated following PANX1 opening after single or multiple SDs evoked by either KCl topical application or non-invasively with optogenetics. The SD-evoked NLRP3 inflammasome activation was observed exclusively in neurons but not microglia or astrocytes. Proximity ligation assay demonstrated that the assembly of the NLRP3 inflammasome occurred as early as 15 min after SD. Genetic ablation of Nlrp3 or Il1b or pharmacological inhibition of PANX1 or NLRP3 ameliorated SD-induced neuronal inflammation, middle meningeal artery dilatation, calcitonin gene-related peptide expression in trigeminal ganglion and c-Fos expression in trigeminal nucleus caudalis. Moreover, multiple SDs induced microglial activation subsequent to neuronal NLRP3 inflammasome activation, which in turn orchestrated with neurons to mediate cortical neuroinflammation, as demonstrated by decreased neuronal inflammation after pharmacological inhibition of microglia activation or blockade of the TLR2/4 receptors. To conclude, single or multiple SDs evoked activation of neuronal NLRP3 inflammasomes and its downstream inflammatory cascades to mediate cortical neuroinflammation and trigeminovascular activation. In the context of multiple SDs, the cortical inflammatory processes could be facilitated by SD-evoked microglia activation. These findings may implicate the potential role of innate immunity in migraine pathogenesis.
Asunto(s)
Inflamasomas , Trastornos Migrañosos , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias , Receptor Toll-Like 2 , Inflamación , Neuronas/metabolismo , Proteínas del Tejido Nervioso , ConexinasRESUMEN
BACKGROUND: The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute treatments for cluster headache are primarily delivered via rapid, non-oral routes (such as inhalation, nasal, or subcutaneous) while preventives include a variety of unrelated treatments such as corticosteroids, verapamil, and galcanezumab. Neuromodulation is becoming an increasingly popular option, both non-invasively such as vagus nerve stimulation when medical treatment is contraindicated or side effects are intolerable, and invasively such as occipital nerve stimulation when medical treatment is ineffective. Clinically, this collection of treatment types provides a range of options for the informed clinician. Scientifically, this collection provides important insights into disease mechanisms. METHODS: Two authors performed independent narrative reviews of the literature on guideline recommendations, clinical trials, real-world data, and mechanistic studies. RESULTS: Cluster headache is treated with acute treatments, bridge treatments, and preventive treatments. Common first-line treatments include subcutaneous sumatriptan and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a preventive treatment. Some newer acute (non-invasive vagus nerve stimulation) and preventive (galcanezumab) treatments have excellent clinical trial data for episodic cluster headache, while other newer treatments (occipital nerve stimulation) have been specifically tested in treatment-refractory chronic cluster headache. Most treatments are suspected to act on the trigeminovascular system, the autonomic system, or the hypothalamus. CONCLUSIONS: The first-line treatments have not changed in recent years, but new treatments have provided additional options for patients.
Asunto(s)
Cefalalgia Histamínica , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Cefalalgia Histamínica/terapia , Oxígeno , Sumatriptán , Sistema Nervioso AutónomoRESUMEN
OBJECTIVE: To investigate whether levcromakalim (a KATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine. METHODS: In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period. RESULTS: A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo (P = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo (P = 0.003). CONCLUSION: Our findings suggest that KATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that KATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of KATP channel blockers in managing post-traumatic headache.Trial Registration: ClinicalTrials.gov Identifier: NCT05243953.
Asunto(s)
Hipersensibilidad , Trastornos Migrañosos , Cefalea Postraumática , Cefalea de Tipo Tensional , Humanos , Cefalea Postraumática/tratamiento farmacológico , Cefalea Postraumática/etiología , Cromakalim/efectos adversos , Canales KATP , Trastornos Migrañosos/tratamiento farmacológico , Cefalea , Método Doble Ciego , Adenosina TrifosfatoRESUMEN
INTRODUCTION: Migraine's astonishing prevalence and preserved genetic background contrast with the definition of a disease and the biological meaning of experiencing recurrent, severe headache attacks is still puzzling. METHODS: To provide a comprehensive explanation of the migraine evolutionary meaning, we review (i) the putative role of the autonomic nervous system in migraine attacks, (ii) the inter-ictal autonomic, functional, and metabolic signature of migraine patients, (iii) the bio-behavioral perspective of pain, and (iv) the allostatic perception of migraine chronification. RESULTS: Migraineurs have inter-ictal cortical hyperexcitability and metabolic dysfunction that predisposes to brain energetic imbalance. Multiple precipitating factors may lead to brain energy consumption over the migraine attack generation threshold. In response, the brain engenders adaptive, evolutionary conserved, autonomic-behavior responses through the antidromic activation of the trigeminovascular system. The sickness behavior and severe pain experienced during migraine attacks result in avoiding mental and physical activity, allowing brain energy restoration. Chronic exposure to stressors may result in an allostatic overload, leading to maladaptive chronic activation of these responses. In this bio-behavioral perspective, the chronification of migraine should be envisioned as a pathological process, whereas the migraine itself should not. CONCLUSION: Migraine has an evolutionary (Darwinian) meaning.
Asunto(s)
Trastornos Migrañosos , Humanos , Trastornos Migrañosos/genética , Encéfalo , Dolor , Sistema Nervioso Autónomo , CefaleaRESUMEN
INTRODUCTION: In the setting of acute COVID-19 infection, headache occurs in 10-60% of patients and may last for days and, in a smaller proportion of patients, weeks (about 10%). However, it is less recognized that headache may also occur after vaccination with a short latency and may persist for a longer period in a still unclear number of patients. METHODS: Retrospective description of headache and course in a case series of 32 outpatients with headache that changed or recurred after COVID-19 vaccination. RESULTS: The majority of patients experienced an exacerbation of migraine headache; rare headache syndromes such as intracranial hypertension or thunderclap headache occurred in 2 patients. Headache manifested in more than 50% of patients within the first 48â¯h after vaccination. Over 50% of patients who received a triptan improved. CONCLUSION: The pathophysiological relationship between vaccination and persistent headache is not yet clearly understood. The short latency, partial efficacy of cortisone, and initial findings showing an increase of various inflammatory markers during the course of headache in COVID infection suggest a possible involvement of the innate immune system and here the inflammasome. Furthermore, the response to triptan in a proportion of patients also indicates activation of the trigeminovascular system.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Cefalea/etiología , Estudios Retrospectivos , Triptaminas/uso terapéuticoRESUMEN
Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation. Dysfunction of ion channels could result in neuronal excitability and peripheral or central sensitization. This narrative review covers the current understanding of the biological mechanisms leading to activation and sensitization of the trigeminovascular pain pathway, with a focus on recent findings on ion channel activation and modulation. Furthermore, we focus on the kynurenine pathway since this system contains kynurenic acid, which is an endogenous glutamate receptor antagonist substance, and it has a role in migraine pathophysiology.
Asunto(s)
Quinurenina , Trastornos Migrañosos , Humanos , Quinurenina/metabolismo , Trastornos Migrañosos/metabolismo , Canales Iónicos/metabolismo , Neuronas/metabolismo , Dolor/metabolismoRESUMEN
BACKGROUND: Although the involvement of calcitonin gene-related peptide (CGRP) in migraines is well-established, its specific role in investigating the aura phase, which often precedes the headache, remains largely unexplored. This study aims to instigate CGRP's potential in triggering aura, thus establishing its role in the early stages of migraine. METHODS: In this open-label, non-randomized, single-arm trial, 34 participants with migraine with aura received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min on a single experimental day. Participants were required to be free of headache and report no use of acute medications 24 h before infusion start. The primary endpoint was the incidence of migraine aura during the 12-hour observational period after the start of infusion. RESULTS: Thirteen (38%) of 34 participants developed migraine aura after CGRP infusion. In addition, 24 (71%) of 34 participants developed migraine headache following CGRP infusion. CONCLUSIONS: Our findings suggest that CGRP could play an important role in the early phases of a migraine attack, including during the aura phase. These insights offer a new perspective on the pathogenesis of migraines with aura. They underscore the need for additional research to further explore the role of CGRP in these initial stages of a migraine attack, and potentially inform future development of therapeutic interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04592952.
Asunto(s)
Epilepsia , Trastornos Migrañosos , Migraña con Aura , Humanos , Péptido Relacionado con Gen de Calcitonina , Migraña con Aura/inducido químicamente , CefaleaRESUMEN
The trigeminal system is considered a prominent actor in brain nociceptive innervation. The trigeminovascular system is mainly composed of pseudounipolar neurons located within the trigeminal ganglion, whose dendrites originate in cerebral blood vessels. Anatomical studies demonstrating anatomical continuity between perivascular fibers and the trigeminal system are lacking. This issue is addressed in this study. Eleven cadaveric heads obtained from a body donation program were fixed in formalin. We performed a microanatomical study of the cavernous carotid-trigeminal interface and a histological examination of the tissue bridges crossing the virtual space between the medial aspect of the trigeminal ganglion and ophthalmic nerve and the lateral aspect of the cavernous segment of the internal carotid artery. Very strong adhesion was observed between the horizontal segment of the artery and the ophthalmic nerve in all specimens. The virtual space in this interface was crossed by a web of delicate filaments. Histological examination demonstrated the presence of nerve fibers in all samples. In this study, the carotid-trigeminal interface has been described in greater detail than ever before and could provide insight into disorders related to the trigeminovascular system. As the present results do not allow the exact nature of the axons to be affirmed, further investigation is necessary.
Asunto(s)
Arteria Carótida Interna , Ganglio del Trigémino , Humanos , CadáverRESUMEN
INTRODUCTION: This review aims to model migraine nociception. METHODS: Personal experience and litterature. RESULTS: Genetic and environmental factors in combination decide whether a person suffers from migraine. Endogenous and/or exogenous factors precipitate the individual attacks. Nociception takes place around blood vessels. There is a growing understanding of the molecular pathophysiological mechanisms of migraine from human provocation studies. Rodent models of migraine are necessary to understand the complex interrelation between the many putatively involved molecules and tissues but their relevance for human migraine is uncertain. The crucial element in migraine nociception is a unit consisting of endothelial cells, vascular smooth muscle cells, perivascular nerve fibers (trigeminal, parasympathetic and sympathetic) and mast cells. Attacks may start outside the brain by humoral or neurogenic activity releasing nociceptive substances around blood vessels. They may also (perhaps more often) start by the brain generating efferent activity in autonomic and somatic nerves. CONCLUSION: Human and rodent studies can quickly uncover the "mystery of migraine".
Asunto(s)
Células Endoteliales , Migraña sin Aura , Humanos , Dolor , Nocicepción/fisiología , Sistema Nervioso AutónomoRESUMEN
BACKGROUND: This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. METHODS: Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. RESULTS: Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. CONCLUSIONS: These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Nociceptores , Animales , Teorema de Bayes , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Masculino , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Fibras Nerviosas Amielínicas , Piperidinas/farmacología , Piridinas/farmacología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/farmacologíaRESUMEN
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.
Asunto(s)
Depresión de Propagación Cortical , Receptores Opioides , Receptores de Serotonina 5-HT1 , Animales , Ratas , Neuronas , Nociceptores , Receptores Opioides/fisiología , Receptores de Serotonina 5-HT1/fisiologíaRESUMEN
BACKGROUND: Calcitonin gene-related peptide release in trigeminovascular system is a pivotal component of neurogenic inflammation underlying migraine pathophysiology. Transient receptor potential channels and voltage-gated KCNQ/Kv7 potassium channels expressed throughout trigeminovascular system are important targets for modulation of calcitonin gene-related peptide release. We investigated the effects of certain transient receptor potential (TRP) channels the vanilloid 1 and 4 (TRPV1 and TRPV4), the ankyrin 1 (TRPA1), and metastatin type 8 (TRPM8), and voltage-gated potassium channel (Kv7) opener retigabine on calcitonin gene-related peptide release from peripheral (dura mater and trigeminal ganglion) and central (trigeminal nucleus caudalis) trigeminal components of rats. METHODS: The experiments were carried out using well-established in-vitro preparations (hemiskull, trigeminal ganglion and trigeminal nucleus caudalis) from male Wistar rats. Agonists and antagonists of TRPV1, TRPV4, TRPA1 and TRPM8 channels, and also retigabine were tested on the in-vitro release of calcitonin gene-related peptide. Calcitonin gene-related peptide concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: Agonists of these transient receptor potential channels induced calcitonin gene-related peptide release from hemiskull, trigeminal ganglion and trigeminal nucleus caudalis, respectively. The transient receptor potential channels-induced calcitonin gene-related peptide releases were blocked by their specific antagonists and reduced by retigabine. Retigabine also decreased basal calcitonin gene-related peptide releases in all preparations. CONCLUSION: Our findings suggest that favorable antagonists of these transient receptor potential channels, or Kv7 channel opener retigabine may be effective in migraine therapy by inhibiting neurogenic inflammation that requires calcitonin gene-related peptide release.
Asunto(s)
Trastornos Migrañosos , Canales de Potencial de Receptor Transitorio , Ratas , Masculino , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Canales de Potencial de Receptor Transitorio/farmacología , Canales Catiónicos TRPV , Inflamación Neurogénica , Ratas Wistar , Ganglio del Trigémino/metabolismo , Trastornos Migrañosos/tratamiento farmacológicoRESUMEN
Transcranial Doppler ultrasonography is used to study intracranial blood flow changes associated with migraine in humans, but whether this method is helpful in preclinical settings is yet unknown. To identify changes in rat intracranial blood flow specific to trigeminovascular activation-a key process in migraine pathophysiology-we measured Doppler indices in the middle cerebral artery and basilar artery before, during, and after dural or somatosensory electrical stimulation. Hemodynamic changes specific to dural stimulation were tested further in separate experiments. After baseline recordings, the animals received cumulative infusions of valproate (100 mg/kg, trice), sumatriptan (0.3, 1, and 3 mg/kg), or saline, and dural stimulation with measurement of Doppler indices was repeated every 10 min for 1 h. Several parameters of blood flow in the rat middle cerebral artery underwent alterations specific to trigeminovascular activation. These changes, however, were insensitive to valproate and sumatriptan and diminished over time. These findings question the reliability of blood flow velocity variations in large intracranial vessels as biological markers of migraine-related processes and do not support the idea of using transcranial Doppler ultrasonography for preclinical screening of antimigraine treatments, at least in the model of acute trigeminovascular activation in rats.
Asunto(s)
Trastornos Migrañosos , Ultrasonografía Doppler Transcraneal , Animales , Velocidad del Flujo Sanguíneo/fisiología , Circulación Cerebrovascular , Humanos , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/tratamiento farmacológico , Ratas , Reproducibilidad de los Resultados , Sumatriptán/farmacología , Sumatriptán/uso terapéutico , Ultrasonografía Doppler Transcraneal/métodos , Ácido Valproico/farmacologíaRESUMEN
OBJECTIVE: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine. METHODS: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period. RESULTS: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale. CONCLUSION: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.
Asunto(s)
Conmoción Encefálica , Trastornos Migrañosos , Cefalea Postraumática , Cefalea de Tipo Tensional , Adulto , Femenino , Humanos , Masculino , Conmoción Encefálica/complicaciones , Péptido Relacionado con Gen de Calcitonina , Cefalea/complicaciones , Trastornos Migrañosos/epidemiología , Cefalea Postraumática/etiología , Cefalea de Tipo Tensional/complicacionesRESUMEN
BACKGROUND: The onset and duration of spontaneous migraine attacks are most often difficult to predict which, in turn, makes it challenging to study the neurobiologic underpinnings of the disease in a controlled experimental setting. To address this challenge, human provocation studies can be used to identify signaling molecules (e.g. calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide) that, upon intravenous or oral administration, induce migraine attacks in people with migraine and mild or no headache in healthy volunteers. This approach has proven to be valid for decades and plays an integral role in mapping signaling pathways underlying migraine pathogenesis and identification of novel drug targets. However, the question arises as to whether the pathogenic mechanisms of provoked and spontaneous migraine attacks differ. In this paper, we provide an opinionated discussion on the similarities and differences between provoked and spontaneous attacks based on the current understanding of migraine pathogenesis. METHODS: The PubMed database was searched in July 2022 for original research articles on human provocation studies that included participants with migraine. The reference lists of originally identified articles were also searched and we selected those we judged relevant. DISCUSSION: People with migraine describe that provoked attacks resemble their spontaneous attacks and can be treated with their usual rescue medication. From a neurobiologic standpoint, provoked and spontaneous migraine attacks appear to be similar, except for the source of migraine-inducing substances (exogenous vs. endogenous source). In addition, provoked attacks can likely not be used to study the events that precede the release of migraine-inducing signaling molecules from sensory afferents and/or parasympathetic efferents during spontaneous attacks.
Asunto(s)
Trastornos Migrañosos , Péptido Relacionado con Gen de Calcitonina/farmacología , Cefalea , Humanos , Polipéptido Hipofisario Activador de la Adenilato-CiclasaRESUMEN
Migraine is a ubiquitous neurologic disease that afflicts people of all ages. Its molecular pathogenesis involves peptides that promote intracranial vasodilation and modulate nociceptive transmission upon release from sensory afferents of cells in the trigeminal ganglion and parasympathetic efferents of cells in the sphenopalatine ganglion. Experimental data have confirmed that intravenous infusion of these vasoactive peptides induce migraine attacks in people with migraine, but it remains a point of scientific contention whether their site of action lies outside or within the central nervous system. In this context, it has been hypothesized that transient dysfunction of brain barriers before or during migraine attacks might facilitate the passage of migraine-inducing peptides into the central nervous system. Here, we review evidence suggestive of brain barrier dysfunction in migraine pathogenesis and conclude with lessons learned in order to provide directions for future research efforts.