| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
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| 9. |
- 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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| 10. |
- Erdling, André, et al.
(författare)
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Differential inhibitory response to telcagepant on αCGRP induced vasorelaxation and intracellular Ca2+ levels in the perfused and non-perfused isolated rat middle cerebral artery
- 2017
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 18:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. Methods: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Results: Abluminal but not luminal αCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10-6 M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. Conclusions: This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non-competitive antagonist at concentrations greater than 10-8 M.
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