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- Edvinsson, Lars
(författare)
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Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache.
- 2004
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 24:8, s. 611-622
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Forskningsöversikt (refereegranskat)abstract
- In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with any of the other neuronal messengers. The purpose of this review is to describe the role of CGRP in the intracranial circulation and to elucidate a possible role for a specific CGRP receptor antagonist in the treatment of primary headaches. Acute treatment with a 5-HT1B/1D agonist (triptan) results in alleviation of the headache and normalization of the cranial venous CGRP levels, in part due to a presynaptic inhibitory effect on sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists with few cardiovascular side-effects. The initial pharmacological profile of such a group of compounds has recently been disclosed. One of these compounds has been found to be efficacious in the relief of acute attacks of migraine.
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- Edvinsson, Lars, et al.
(författare)
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The blood-brain barrier in migraine treatment.
- 2008
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 28, s. 1245-1258
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Tidskriftsartikel (refereegranskat)abstract
- Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized arteriography method. The drugs, given both luminally and abluminally, provide important notions regarding antimigraine site of action, probably abluminal to the BBB. The problems with the BBB in animal models designed to study the pathophysiology, acute treatment models and preventive treatments are discussed with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy.
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| 5. |
- Edvinsson, M-L, et al.
(författare)
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Comparison of CGRP and NO responses in the human peripheral microcirculation of migraine and control subjects.
- 2008
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 28:5, s. 563-566
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Tidskriftsartikel (refereegranskat)abstract
- Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are two molecules shown to have a role in migraine pathophysiology. Our objective was to test the hypothesis that migraine subjects are particularly sensitive to these signal molecules. The cutaneous microvascular responses to endothelial and non-endothelial dependent dilators were tested using laser Doppler flowmetry in combination with iontophoresis. The blood flow responses to iontophoretic administration of the endothelium-dependent vasodilator acetylcholine (ACh), or to the endothelium-independent dilators sodium nitroprusside (SNP) and CGRP, and to local warming (44 degrees C) were compared in this controlled trial. The design was that of two arms: patients diagnosed with migraine without aura (n = 9) for >10 years were compared with nine healthy subjects matched for age and gender (seven female and two male, age range 30-60 years). Iontophoretic administration resulted in local vasodilation. ACh induced a relaxation of 1225 +/- 245% (relative to baseline) in controls and 1468 +/- 368% (P > 0.05) in migraine. The responses to SNP were 873 +/- 193% in controls and 1080 +/- 102% (P > 0.05) in migraine subjects. The responses to CGRP were 565 +/- 89% in controls and 746 +/- 675% (P > 0.05) in migraine patients. The responses to local heating which induced maximum dilation did not differ between the groups (1976 +/- 314% for controls and 1432 +/- 226% in migraine; P > 0.05. We conclude that there is no change in the microvascular responsiveness of the subcutaneous microvasculature in migraine.
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- Frese, A, et al.
(författare)
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Calcitonin gene-related peptide in cervicogenic headache
- 2005
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 25:9, s. 700-703
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Tidskriftsartikel (refereegranskat)abstract
- Trigeminovascular activation is involved in the pathophysiology of migraine and cluster headache. The marker evaluated best for trigeminovascular activation is calcitonin gene-related peptide (CGRP) in the cranial circulation. It is unknown whether trigeminovascular activation plays any role in cervicogenic headache (CEH). The objective of this study was to investigate CGRP plasma levels in CEH patients in relation to headache state. To compare plasma CGRP levels between the peripheral and the cranial circulation. Blood from both external jugular veins and from the antecubital vein was drawn from 11 patients with CEH. Plasma CGRP levels were measured by radioimmunoassay. No difference was found between CGRP levels assessed on days with and without headache. There was no difference beween CGRP levels from the symptomatic and the asymptomatic external jugular vein and the antecubital vein. There is no evidence for an activation of the trigeminovascular system in CEH. In certain cases, clinical differentiation between CEH and migraine without aura is difficult. Plasma CGRP levels might serve as a biological marker to distinguish the two headache entities.
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- Kruuse, C., et al.
(författare)
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Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers
- 2010
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 30:4, s. 467-474
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Tidskriftsartikel (refereegranskat)abstract
- The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 mu g kg(-1) min(-1)) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 +/- 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 mu g kg(-1) min(-1), median peak headache intensity was 4 (range 2-6) (P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 +/- 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.
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- Liu, Y, et al.
(författare)
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Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats.
- 2009
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 29, s. 935-948
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Tidskriftsartikel (refereegranskat)abstract
- To examine the ascending projections from the headache-related trigeminocervical complex in rats, biotinylated dextran amine (BDA) was injected into the ventrolateral dorsal horn of segments C1 and C2, a region previously demonstrated to receive input from sensory nerves in cranial blood vessels. Following injections into laminae I-II, BDA-labelled terminations were found bilaterally in several nuclei in the pons and the midbrain, including the pontine reticular nucleus, the parabrachial nuclei, the cuneiform nucleus and the periaqueductal grey. In the diencephalon, terminations were confined to the contralateral side and evident foremost in the posterior nuclear group, especially its triangular part, and in the ventral posteromedial nucleus. Following injections extending through laminae I-IV, anterograde labelling was more extensive. Some of the above regions are likely to be involved in the central processing of noxious signals of craniovascular origin and therefore putatively involved in mechanisms associated with primary headaches.
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| 9. |
- Petersen, KA, et al.
(författare)
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Presence and function of the calcitonin gene-related peptide receptor on rat pial arteries investigated in vitro and in vivo
- 2005
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 25:6, s. 424-432
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Tidskriftsartikel (refereegranskat)abstract
- Calcitonin gene-related peptide (CGRP) and related peptides may be involved in migraine pathogenesis. To understand their vasomotor role in the cerebral circulation, we performed two studies, a pressurized arteriography study of the middle cerebral artery (MCA) and a genuine closed cranial window (gCCW) in vivo study. Using the pressurized arteriography model rat MCAs were mounted on micropipettes, pressurized to 85 mmHg and luminally perfused. The diameter responses to luminally and abluminally applied rat-alpha CGRP, rat-beta CGRP, amylin and adrenomedullin were compared with the resting diameter. Only abluminally applied CGRP induced dilation of the cerebral arteries; E-max for alpha CGRP and beta CGRP were 35 +/- 0.5% and 10.8 +/- 0.2%. These responses were blocked by CGRP(8-37). The gCCW model allowed videomicroscopic visualization of the pial vessels in anaesthetized rats. Changes in vessel diameter to intravenously administered alpha CGRP and beta CGRP were compared with pre-infusion baseline. Intravenous infusion of alpha CGRP and beta CGRP in the highest dose induced dilation of the cerebral cortical pial arteries/arterioles of 40.3 +/- 7.5% and 49.1 +/- 8.4%, respectively. However, this was probably secondary to a decrease in blood pressure of 44.8 +/- 3.3 mmHg and 49.2 +/- 3.3 mmHg. Our results suggest that CGRP receptors are probably functional on the smooth muscle cells and not on the endothelium of rat cerebral arteries.
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- Smith, D, et al.
(författare)
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An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres
- 2002
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 22:6, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- 5-HT1D (but not 5-HT1B )-receptor immunoreactivity (i.r.) can be detected on trigeminal fibres within the spinal trigeminal tract of the human brainstem. The present study used immunohistochemical and morphometric techniques to determine the proportions of trigeminal fibres expressing substance P, CGRP or 5-HT1D -receptor immunoreactivities. Co-localization studies between 5-HT1D -receptor and substance P- or CGRP-i.r. were also performed. Brainstem material was obtained with consent (four donors) and the total number of immunoreactive fibres within the trigeminal tract was estimated using random field sampling. A greater proportion of fibres (>1 mum diameter) expressed CGRP-i.r. (80 +/- 6%) compared with substance P-i.r. (46 +/- 7%) or 5-HT1D -receptor-i.r. (25 +/- 1%). 5-HT1D -receptor-i.r. was co-localized on some CGRP- or substance P-i.r. fibres. This suggests that 5-HT1D -receptors can regulate the release of CGRP and substance P and may be relevant to the clinical effectiveness of 5-HT1B/1D -receptor agonists in the treatment of migraine and other cranial pain syndromes.
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