| 1. |
- Grände, Gustaf, et al.
(författare)
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Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds
- 2014
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine. A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E-2 (PGE(2)), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean E-max(%) at the highest concentration of each substance to the E-max(%) of NaCl buffer. In the human experiments, all substances except PACAP-38 had an E-max (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF(2 alpha), similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries. Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.
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| 2. |
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| 3. |
- Mitsikostas, Dimos D., et al.
(författare)
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Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation
- 2014
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients' life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years. Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28.2%) international investigators commented during two rounds. Refractory CCH is described in the present consensus as a situation that fulfills the criteria of ICHD-3 beta for CCH with at least three severe attacks per week despite at least three consecutive trials of adequate preventive treatments. The condition is rare, but difficult to manage and invasive treatments may be needed. The consensus addresses five specific clinical and paraclinical diagnostic criteria followed by three notes and specific comments. Although refractory CCH may be not a separate identity these specific diagnostic criteria should help clinicians and investigators to improve patient's quality of life.
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| 4. |
- Jonsson, Pernilla, 1978, et al.
(författare)
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Holding on to the indispensable medication –A grounded theory on medication use from the perspective of persons with medication overuse headache
- 2013
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 14:43, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Medication overuse headache (MOH) is a chronic headache disorder, caused by overuse of acute medication. To date, it remains unclear why some people overuse these medications. The aim of this qualitative study was to explore how individuals with MOH use medications and other strategies to manage headaches in their daily lives, and their thoughts about their own use of acute medication. Our intention was to develop a theoretical model about the development of MOH, from the perspective of those with MOH. Methods: Data collection and analysis were conducted according to grounded theory methodology. The participants were recruited via newspaper advertisements. Fourteen persons with MOH were interviewed in individual qualitative interviews. Results: The basic process leading to medication overuse was holding on to the indispensable medication. The acute medication was indispensable to the participants because they perceived it as the only thing that could prevent headaches from ruining their lives. The participants perceived headaches as something that threatened to ruin their lives. As a result, they went to great lengths trying to find ways to manage it. They tried numerous strategies. However, the only strategy actually perceived as effective was the use of acute medication and they eventually became resigned to the idea that it was the only effective aid. The acute medication thus became indispensable. Their general intention was to use as little medication as possible but they found themselves compelled to medicate frequently to cope with their headaches. They did not like to think about their medication use and sometimes avoided keeping track of the amount used. Conclusions: This qualitative study adds understanding to the process via which MOH develops from the perspective of those having MOH. Such knowledge may help bridge the gap between the perspectives of patients and health-care professionals.
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| 5. |
- Larsson, Bo, et al.
(författare)
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Headache prevalence and characteristics among adolescents in the general population : a comparison between retrospect questionnaire and prospective paper diary data
- 2014
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 15, s. 80-
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the present school-based study, a convenience sample of 237 adolescents in grade 6-9 and second year in high school (age 12-18 years) was recruited from a city and a smaller town. The aim of the study was to compare information on the prevalence and various characteristics of headaches not related to disease in a retrospect questionnaire and prospective daily recordings of headaches in a standard paper diary during a 3-week period. Methods: Besides headache severity, number of headache days, intensity levels and duration of headache episodes were estimated with both assessment methods. Most of the school children suffered from tension-type headaches and a smaller portion of migraine attacks. Results: The overall results showed that school children significantly (p < 0.001) overestimated headache intensity in questionnaires as compared to diary recordings, whereas they underestimated frequency (p < 0.001) and duration (p < 0.001) of headaches. While the correlations on headache severity, frequency and duration between retrospect information in questionnaires and prospective diary recordings were low, the agreement varied with levels of headache characteristics. Conclusions: Our findings concur well with results from a few similar community studies on headache complaints in school-aged children. We recommend that prospective recordings in diaries should be systematically used in clinical practice but also in epidemiological surveys to increase the validity and reliability in estimates of point prevalence of headache complaints in children and adolescents.
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| 6. |
- Louca, Sofia, et al.
(författare)
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Serotonin, glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles : a microdialysis study
- 2014
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Ingår i: Journal of Headache and Pain. - : Springer. - 1129-2369 .- 1129-2377. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline-induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect. METHODS: Healthy participants, 15 men and 15 aged-matched women (25.7 ± 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections. RESULTS: The median (IQR) peak pain intensity (0-100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05). CONCLUSIONS: 5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations.
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| 7. |
- Tronvik, Erling, et al.
(författare)
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The relationship between headache and religious attendance (the Nord-Trøndelag health study- HUNT)
- 2014
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Ingår i: Journal of Headache and Pain. - : Springer. - 1129-2369 .- 1129-2377. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Religious belief can be used as a pain coping strategy. Our purpose was to evaluate the relationship between headache and religious activity using prospective data from a large population-based study.METHODS: This longitudinal cohort study used data from two consecutive surveys in the Nord-Trøndelag Health Survey (HUNT 2 and 3) performed in 1995-1997; and 2006-2008. Among the 51,383 participants aged ≥ 20 years who answered headache questions at baseline, 41,766 were eligible approximately 11 years later. Of these, 25,177 (60%) completed the question in HUNT 3 regarding religious activity. Frequent religious attendees (fRA) (used as a marker of stronger religious belief than average) were defined as those who had been to church/prayer house at least once monthly during the last six months.RESULTS: In the multivariate analyses, adjusting for known potential confounders, individuals with headache 1-14 days/month in HUNT 2 were more likely to be fRA 11 years later than headache-free individuals. Migraine at baseline predisposed more strongly to fRA at follow-up (OR = 1.25; 95% CI 1.19-1.40) than did non-migrainous headache (OR = 1.13; 95% 1.04-1.23). The odds of being fRA was 48% increased (OR 1.48; 95% 1.19-1.83) among those with migraine 7-14 days/month at baseline compared to subjects without headache. In contrast, headache status at baseline did not influence the odds of being frequent visitors of concerts, cinema and/or theatre at follow-up 11 years later.CONCLUSIONS: In this prospective study, headache, in particular migraine, at baseline slightly increased the odds of being fRA 11 years later.
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| 8. |
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| 9. |
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| 10. |
- Affatato, Oreste, et al.
(författare)
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Major sex differences in migraine prevalence among occupational categories : a cross-sectional study using UK Biobank
- 2021
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Ingår i: Journal of Headache and Pain. - : Springer Nature. - 1129-2369 .- 1129-2377. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Christensen, R. H., et al.
(författare)
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Imaging the inflammatory phenotype in migraine
- 2022
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Several preclinical and clinical lines of evidence suggest a role of neuroinflammation in migraine. Neuroimaging offers the possibility to investigate and localize neuroinflammation in vivo in patients with migraine, and to characterize specific inflammatory constituents, such as vascular permeability, and macrophage or microglia activity. Despite all imaging data accumulated on neuroinflammation across the past three decades, an overview of the imaging evidence of neuroinflammation in migraine is still missing. We conducted a systematic review in the Pubmed and Embase databases to evaluate existing imaging data on inflammation in migraine, and to identify gaps in the literature. We included 20 studies investigating migraine without aura (N = 4), migraine with aura (N = 8), both migraine with and without aura (N = 3), or hemiplegic migraine (N = 5). In migraine without aura, macrophage activation was not evident. In migraine with aura, imaging evidence suggested microglial and parameningeal inflammatory activity. Increased vascular permeability was mostly found in hemiplegic migraine, and was atypical in migraine with and without aura. Based on the weight of existing and emerging data, we show that most studies have concentrated on demonstrating increased vascular permeability as a marker of neuroinflammation, with tools that may not have been optimal. In the future, novel, more sensitive techniques, as well as imaging tracers delineating specific inflammatory pathways may further bridge the gap between preclinical and clinical findings.
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| 15. |
- Christiansen, Isabella Mai, et al.
(författare)
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Dual action of the cannabinoid receptor 1 ligand arachidonyl-2′-chloroethylamide on calcitonin gene-related peptide release
- 2022
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Based on the current understanding of the role of neuropeptide signalling in migraine, we explored the therapeutic potential of a specific cannabinoid agonist. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2′-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate Gi/o-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition. Methods: The experiments were performed using the hemi-skull model and dissected TGs from male Sprague-Dawley rats. CGRP release was induced by either 60 mM K+ (for depolarization-induced stimulation) or 100 nM capsaicin (for transient receptor potential vanilloid 1 (TRPV1) -induced stimulation) and measured using an enzyme-linked immunosorbent assay. The analysis of CGRP release data was combined with immunohistochemistry in order to study the cellular localization of CB1, cannabinoid receptor type 2 (CB2), CGRP and receptor activity modifying protein 1 (RAMP1), a subunit of the functional CGRP receptor, in the TG. Results: CB1 was predominantly expressed in neuronal somas in which colocalization with CGRP was observed. Furthermore, CB1 exhibited colocalization with RAMP1 in neuronal Aδ-fibres but was not clearly expressed in the CGRP-immunoreactive C-fibres. CB2 was mainly expressed in satellite glial cells and did not show substantial colocalization with either CGRP or RAMP1. Without stimulation, 140 nM ACEA per se caused a significant increase in CGRP release in the dura but not TG, compared to vehicle. Furthermore, 140 nM ACEA did not significantly modify neither K+- nor capsaicin-induced CGRP release. However, when the TRPV1 blocker AMG9810 (1 mM) was coapplied with ACEA, K+-induced CGRP release was significantly attenuated in the TG and dura. Conclusions: Results from the present study indicate that ACEA per se does not exhibit antimigraine potential due to its dual agonistic properties, resulting in activation of both CB1 and TRPV1, and thereby inhibition and stimulation of CGRP release, respectively.
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| 16. |
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| 17. |
- Csáti, A, et al.
(författare)
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Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion.
- 2015
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 16:99
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Tidskriftsartikel (refereegranskat)abstract
- The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG.
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| 18. |
- Dawson, Andreas, et al.
(författare)
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Dopamine in plasma : a biomarker for myofascial TMD pain?
- 2016
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Ingår i: Journal of Headache and Pain. - : Springer. - 1129-2369 .- 1129-2377. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dopaminergic pathways could be involved in the pathophysiology of myofascial temporomandibular disorders (M-TMD). This study investigated plasma levels of dopamine and serotonin (5-HT) in patients with M-TMD and in healthy subjects. METHODS: Fifteen patients with M-TMD and 15 age- and sex-matched healthy subjects participated. The patients had received an M-TMD diagnosis according to the Research Diagnostic Criteria for TMD. Perceived mental stress, pain intensity (0-100-mm visual analogue scale), and pressure pain thresholds (PPT, kPa) over the masseter muscles were assessed; a venous blood sample was taken. RESULTS: Dopamine in plasma differed significantly between patients with M-TMD (4.98 ± 2.55 nM) and healthy controls (2.73 ± 1.24 nM; P < 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P < 0.001) and had lower PPTs (P < 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P < 0.05) and perceived mental stress (r = 0.34, n = 28, P < 0.05). CONCLUSIONS: The results suggest that peripheral dopamine might be involved in modulating peripheral pain. This finding, in addition to reports in other studies, suggests that dopaminergic pathways could be implicated in the pathophysiology of M-TMD but also in other chronic pain conditions. More research is warranted to elucidate the role of peripheral dopamine in the pathophysiology of chronic pain.
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| 19. |
- Deen, Marie, et al.
(författare)
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Blocking CGRP in migraine patients – a review of pros and cons
- 2017
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 18, s. 1-9
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Forskningsöversikt (refereegranskat)abstract
- Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.
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| 20. |
- Edvardsson, Bengt, et al.
(författare)
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Cerebral infarct presenting with thunderclap headache.
- 2009
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 10, s. 207-209
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Tidskriftsartikel (refereegranskat)abstract
- A 73-year-old man presented with a thunderclap headache (TCH), suggesting a subarachnoid haemorrhage. Neurological examination, computer tomography of the head, and cerebrospinal fluid examination were normal. Magnetic resonance imaging of the brain revealed a supratentorial cerebral infarct. No cerebral aneurysm could be detected. A TCH can be the presenting feature of many conditions. A formula for the diagnostic assessment of TCH should be established. The management of this type of headache is controversial. Articles differ in their conclusions and recommendations. An expansion of routine investigations should be performed in cases where the neurological examination, cerebrospinal fluid analysis, and computer tomography are normal. A TCH can be the primary clinical feature of a supratentorial cerebral infarct.
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| 21. |
- Edvardsson, Bengt, et al.
(författare)
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Reversible cerebral vasoconstriction syndrome associated with autonomic dysreflexia.
- 2010
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 11, s. 277-280
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Tidskriftsartikel (refereegranskat)abstract
- A 32-year-old man with a residual spastic quadriparesis from a traumatic C5-C6 fracture experienced a severe thunderclap headache. The medical history revealed an episode of autonomic dysreflexia (AD) due to neurogenic bladder/urinary tract infection (UTI). Blood pressure monitoring at admission revealed hypertension; blood pressure reaching 160/100 mmHg (average blood pressure in these patients and also in this patient being 90/60 mmHg). CT scan of the head, cerebrospinal fluid examination, CT angiography and MR angiography of the brain vessels were normal. Another UTI and a subsequent spell of AD were diagnosed. The patient continued to experience recurrent thunderclap headaches. Selective catheter cerebral angiography revealed multiple calibre changes in the intracranial blood vessels. A diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) due to AD was considered. A magnetic resonance imaging (MRI) of the brain after 2 weeks revealed ischaemic changes in the left hemisphere. Follow-up brain MRI after 3 weeks showed reduction in size of the ischaemic changes, and catheter angiography after 6 weeks demonstrated improvement/normalization. A diagnosis of RCVS could be established. Repeated MRI/CT of the brain after 6 months demonstrated a large infarction in the left hemisphere. RCVS has been reported to occur in various clinical settings. It can occur in the setting of AD in patients with traumatic cervical cord injury. Prompt recognition of RCVS may be of vital importance to avoid further morbidity in patients with spinal cord injury.
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| 22. |
- Edvinsson, Jacob C.A., et al.
(författare)
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C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system
- 2019
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1). METHODS: With specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay. RESULTS: Antibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C- and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers. CONCLUSION: We observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.
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| 23. |
- Edvinsson, Jacob C.A., et al.
(författare)
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MERTK in the rat trigeminal system : a potential novel target for cluster headache?
- 2024
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Ingår i: Journal of Headache and Pain. - 1129-2369 .- 1129-2377. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache. Graphical Abstract: (Figure presented.)
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| 24. |
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| 25. |
- Edvinsson, Lars, et al.
(författare)
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PACAP and its role in primary headaches
- 2018
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 19:1
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Forskningsöversikt (refereegranskat)abstract
- Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics.
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