Dual Inhibition of FAAH and MAGL Counteracts Migraine-like Pain and Behavior in an Animal Model of Migraine

The endocannabinoid system exerts an important role in pain processing and modulation. Modulation of the system with hydrolase inhibitors of anandamide (AEA) or 2-arachidonyl glycerol (2-AG) has proved effective in reducing migraine-like features in animal models of migraine. Here, we investigated the effect of dual inhibition of the AEA and 2-AG catabolic pathways in the nitroglycerin-based animal model of migraine. The dual inhibitor JZL195 was administered to rats 2 h after nitroglycerin or vehicle injection. Rats were then exposed to the open field test and the orofacial formalin test. At the end of the tests, they were sacrificed to evaluate calcitonin gene-related peptide (CGRP) serum levels and gene expression of CGRP and cytokines in the cervical spinal cord and the trigeminal ganglion. The dual inhibitor significantly reduced the nitroglycerin-induced trigeminal hyperalgesia and pain-associated behavior, possibly via cannabinoid 1 receptors-mediated action, but it did not change the hypomotility and the anxiety behaviors induced by nitroglycerin. The decreased hyperalgesia was associated with a reduction in CGRP and cytokine gene expression levels in central and peripheral structures and reduced CGRP serum levels. These data suggest an antinociceptive synergy of the endocannabinoid action in peripheral and central sites, confirming that this system participates in reduction of cephalic pain signals.

Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies.

Rates of hospitalizations for migraines and other cephalic algias syndromes is children between 2014 and 2020

Introduction: Migraine is the most common chronic headache in childhood, however, it is still little diagnosed in the pediatric group. Early crises can be very early, at 6 months of age. It may present in different ways according to the age group of the child and may or may not resemble the clinical picture of the associated manifestations that may aid in diagnosis. Methods and Objectives: The study used data available on the DataSus, in the category of hospitalization by the CID-10, in the group of less than 1 year, between 1 and 4 years, 5 and 9 years and 10 and 14 years, in the period from 2014 to 2020, to discuss the diagnosis of migraines and compare the prevalence of hospitalizations among children . Results: Between 2014 and 2020, the age group with the highest rate of hospitalization for migraine and other cephalic pain syndromes was 10-14 years, with an average of 57,13%, followed by 5-9 years (32,75%), 1-4 years (8,95%) and below 1 year (1,57%). Conclusion: Migraine has a semiological aspect that makes it difficult to identify in the pediatric group: symptoms. How diagnosis depends on a subjective report, children, especially the younger ones, become underdiagnosed. This can justify the higher incidence of hospitalizations among older children, with greater communication skills and a better description. Another factor is the absence of skilled professionals. Adaptation is necessary to assist in diagnosis, such as: associated clinical manifestations; Note; use of semi-structured interrogation and playful scales to spread the pain.

Economic impact of hospitalizations for migraine and other cephalic pain syndromes to the Brazilian Unified Health System

Background: Headache disorders are the third most frequent complaint in ambulatory care facilities, leading to an important loss of healthy years of life. Thus, it is important to study the factors related to hospitalizations due to these syndromes in Brazil. Objective: To describe the profile of hospitalizations due to migraine and other cephalic pain syndromes. Design and methods: This is an ecological study, based on secondary data with a descriptive approach. Data were collected from DATASUS regarding the number of hospitalizations, days spent in hospital, average cost per hospital stay, total amount of expenses, besides sex and age of hospitalized pacients due to migraine and other cephalic pain syndromes from 2011-2020. Results:78.058 hospitalizations were registered, with Southeast region’s prevalence (35.7%). The female and the economically active population (15-64 years) stand out in these results (65.8% and 79.9% respectively). The average permanence was of 3.84 days in SUS and the average value per hospital stay was R$ 407.77. The total amount spent on hospital services was R$ 28,153,255.86. Conclusion: The present study indicates a female and economically active population prevalence in hospitalizations. And also point out a Southeast region’s predominance in total amount of hospitalizations and second place regarding the costs on hospital services.

Overview of hospital admissions for migraine and other cephalic pain syndromes in Brazil and regions, 2015 to 2019

INTRODUCTION: Headache is defined as a pain in the cephalic segment, and is the fourth cause of demand for emergency care. In Brazil, 98% of women and 95% of men will suffer some episode during their lives. It causes physical, social, labor, and economic damage, and is the third leading cause of years lived with disability. Thus, it is relevant to investigate hospital admissions for migraine and other cephalic pain syndromes. OBJECTIVES: To analyze hospital morbidity due to migraine and other cephalic pain syndromes in Brazil between 2015 and 2019. METHODS: Epidemiological, retrospective, descriptive study, carried out through the Hospital Information System (DATASUS). Variables: sex, ethnicity, age, hospital stay, costs and deaths. RESULTS: Registered 49,508 hospitalizations for migraine and other cephalic pain syndromes from 2015-2019; predominantly women (65.7%), between 20-39 years (37.3%), 40-59 years (29.4%), which occurred mainly in the Southeast (33.1%) and South (23.6%) regions. The average cost per hospitalization was R$ 421.50. The mean hospital stay was 3.9 days, ranging from 3.1 days in the South to 4.8 days in the Northeast, with no differences between genders. There were 384 deaths, of which 56.3% were women. CONCLUSION: The morbidity profile due to cephalic pain syndromes is composed of women, aged 20-39 years, living in the Southeast region. It is important to intensify investments in prevention, diagnosis and treatment, seeking to reduce hospitalizations, the impact on the health system and to improve the patient’s quality of life.

Neuropeptide FF receptor 2 inhibits capsaicin-induced CGRP Upregulation in mouse trigeminal ganglion

Background Stimulation of trigeminovascular pathway is widely used to establish the headache animal model. Headache is a common neurological disorder, in which symptomatic attacks are mediated by calcitonin-gene-related peptide (CGRP). CGRP is synthesized and released from the trigeminal ganglion to transmit pain signals under stimulation. On the other hand, Neuropeptide FF (NPFF) is a candidate transmitter/modulator for migraine, and stimulation of its receptor, NPFFR2, increases the expression and release of CGRP in mice sensory neurons. Here, we investigate the impact of NPFFR2 on trigeminal CGRP level in a capsaicin-induced headache mouse model. Methods Mice were intracisternally injected with capsaicin into the cisterna magna to activate the trigeminovascular pathway and induce headache symptoms. Mice pretreated with Npffr2-shRNA or NPFFR2 knockouts were adopted to test the impact of NPFFR2 on capsaicin-induced CGRP upregulation in trigeminal ganglion. The gene silencing effect of Npffr2-shRNA in trigeminal ganglion was confirmed by real-time PCR. Trigeminal CGRP level was determined by immunofluorescence staining, and the percentage of CGRP-positive cell was calculated after setting the signal intensity threshold by Image J software. Amount of trigeminal CGRP in NPFFR2 overexpressed mice was also measured by CGRP ELISA. Findings Infusion of capsaicin into the cisterna magna upregulated the CGRP in trigeminal ganglion and induced spontaneous pain behaviors including the reduction of locomotor activity and the increase of freezing behavior. Intracisternal injection of Npffr2-shRNA reduced the mRNA of Npffr2 in trigeminal ganglion. Mice pretreatment with Npffr2-shRNA prevented capsaicin-induced CGRP upregulation in trigeminal ganglion. Similarly, CGRP upregulation was also reduced in NPFFR2 knockout mice. On the contrary, trigeminal CGRP was increased in NPFFR2 overexpressed mice. Conclusions Reducing the level of NPFFR2 leads to the downregulation of capsaicin-induced CGRP in trigeminal ganglion, which would consequently attenuate the activation of trigeminovascular pathway. Thus, NPFFR2 could serve as a potential target for neuromodulation of cephalic pain.

Resting state connectivity between default mode network and insula encodes acute migraine headache

Background Previous functional MRI studies have revealed that ongoing clinical pain in different chronic pain syndromes is directly correlated to the connectivity strength of the resting default mode network (DMN) with the insula. Here, we investigated seed-based resting state DMN-insula connectivity during acute migraine headaches. Methods Thirteen migraine without aura patients (MI) underwent 3 T MRI scans during the initial six hours of a spontaneous migraine attack, and were compared to a group of 19 healthy volunteers (HV). We evaluated headache intensity with a visual analogue scale and collected seed-based MRI resting state data in the four core regions of the DMN: Medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and left and right inferior parietal lobules (IPLs), as well as in bilateral insula. Results Compared to HV, MI patients showed stronger functional connectivity between MPFC and PCC, and between MPFC and bilateral insula. During migraine attacks, the strength of MPFC-to-insula connectivity was negatively correlated with pain intensity. Conclusion We show that greater subjective intensity of pain during a migraine attack is associated with proportionally weaker DMN-insula connectivity. This is at variance with other chronic extra-cephalic pain disorders where the opposite was found, and may thus be a hallmark of acute migraine head pain.

Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention

Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.