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Peter J. Goadsby - One of the best experts on this subject based on the ideXlab platform.
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Migraine, Pathophysiology of
Encyclopedia of the Neurological Sciences, 2020Co-Authors: S. Akerman, Peter J. GoadsbyAbstract:Migraine is a common and complex disorder of the brain. Migraine pain is undoubtedly a consequence of activation of the trigeminoparasympathetic System, including the efferent projection to the cranial vasculature and dura mater and the afferent projection to the central trigeminal nucleus. However, its full clinical manifestation also suggests activation in brainstem and diencephalic structures. This article will integrate what is known about the anatomy and physiology of the Trigeminovascular System and its connections to these other brain regions, and how this may support our understanding of migraine from a clinical perspective.
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Zolmitriptan: differences from sumatriptan.
Current Medical Research and Opinion, 2020Co-Authors: Peter J. Goadsby, Christopher J. BoesAbstract:SUMMARYZolmitriptan is a potent 5-HT1B/1D agonist whose targets include the peripheral and central components of the Trigeminovascular System. It is generally well-tolerated and has dose-dependent efficacy in the treatment of migraine. The 2.5 mg dose is felt to provide the best balance between efficacy and adverse events. In a direct comparative study, the 2 h headache response rate for zolmitriptan 2.5 mg was statistically superior to sumatriptan 25 and 50 mg, although at 3.3% not clinically significant. Two comparative studies have found no difference in adverse event frequency between zolmitriptan and sumatriptan.
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Cerebral Circulation: Autonomic Influences
Primer on the Autonomic Nervous System, 2020Co-Authors: Peter J. GoadsbyAbstract:Publisher Summary This chapter discusses neurovascular influences on the brain circulation, emphasizing extrinsic autonomic nervous influences. The neural innervation of the brain provides a means by which brain vessel caliber can be altered without changes in perfusion pressure, local metabolic needs, or arterial blood gases. The extrinsic Systems, although arising in the brain, pass out of the brain to traverse peripheral nerves returning to innervate large intracranial and pial vessels. It is the extrinsic System that is the branch of the autonomic nervous System (ANS) that influences brain blood flow. The third component of the extrinsic innervation is the sensory innervation from the trigeminal nerve: the Trigeminovascular System. The Trigeminovascular System has important antidromic and reflex orthodromic vasodilator effects on the cerebral circulation; its reflex connections act through the parasympathetic outflow. The parasympathetic innervation represents the most powerful of the neural vasodilator influences on the cerebral circulation.
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Calcitonin Gene-Related Peptide Antagonists as Treatments of Migraine and Other Primary Headaches
Drugs, 2005Co-Authors: Peter J. GoadsbyAbstract:Calcitonin gene-related peptide (CGRP) is a potent neuromodulator that is expressed in the Trigeminovascular System and is released into the cranial circulation in various primary headaches. CGRP is released in migraine, cluster headache and paroxysmal hemicrania. The blockade of its release is associated with the successful treatment of acute migraine and cluster headache. CGRP receptor blockade has recently been shown to be an effective acute anti-migraine strategy and is non-vasoconstricting in terms of the mechanism of action. The prospect of a non-vasoconstricting therapy for acute migraine offers a real opportunity to patients, and perhaps more importantly, provides a therapeutic rationale to reinforce migraine as a neurological disorder.
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the Trigeminovascular System in humans pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Peter J. GoadsbyAbstract:Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the Trigeminovascular System, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the Systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.
Lars Edvinsson - One of the best experts on this subject based on the ideXlab platform.
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Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries.
Cephalalgia, 2019Co-Authors: Eloísa Rubio-beltrán, Antoinette Maassenvandenbrink, Kayi Chan, A.h. Jan Danser, Lars EdvinssonAbstract:BackgroundMigraine has been associated with a dysfunctional activation of the Trigeminovascular System. Calcitonin gene-related peptide, a neuropeptide released from the trigeminal nerve fibres, ha...
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immunohistochemical localization of the calcitonin gene related peptide binding site in the primate Trigeminovascular System using functional antagonist antibodies
Neuroscience, 2016Co-Authors: Silke Miller, Karin Warfvinge, Mary Dovlatyan, Cen Xu, Lars EdvinssonAbstract:Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a neuromodulator implicated in the pathophysiology of migraine. It binds to the extracellular domains of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 1 that together form the CGRP receptor. Antagonist antibodies against CGRP and its binding site at the receptor are clinically effective in preventing migraine attacks. The blood-brain barrier penetration of these antagonist antibodies is limited, suggesting that a potential peripheral site of action is sufficient to prevent migraine attacks. To further understand the sites of CGRP-mediated signaling in migraine, we used immunohistochemical staining with recently developed antagonist antibodies specifically recognizing a fusion protein of the extracellular domains of RAMP1 and CLR that comprise the CGRP binding pocket at the CGRP receptor in monkey and man. We confirmed binding of the antagonist antibodies to human vascular smooth muscle cells (VSMCs) of dural meningeal arteries and neurons in the trigeminal ganglion, both of which are likely sites of action for therapeutic antibodies in migraine patients. We further used one of these antibodies for detailed mapping on cynomolgus monkey tissue and found antagonist antibody binding sites at multiple levels in the Trigeminovascular System: in the dura mater VSMCs, in neurons and satellite glial cells in the trigeminal ganglion, and in neurons in the spinal trigeminal nucleus caudalis. These data reinforce and clarify our understanding of CGRP receptor localization in a pattern consistent with a role for CGRP receptors in trigeminal sensitization and migraine pathology.
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The Journey to Establish CGRP as a Migraine Target: A Retrospective View.
Headache, 2015Co-Authors: Lars EdvinssonAbstract:In this retrospective, Dr. Lars Edvinsson recounts early steps and milestones in our understanding of the neuropeptide calcitonin gene-related peptide (CGRP) in the Trigeminovascular System and its role in migraine. The discovery of the presence and function of CGRP and other neuropeptides in the cerebral vasculature and its sensory innervation is described. He relates the seminal finding that CGRP is uniquely released during migraine and the journey to develop blockers of CGRP effects. Now, over 30 years since its discovery, CGRP has become the target for a number of promising novel treatments for migraine patients.
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A second trigeminal CGRP receptor: function and expression of the AMY1 receptor
Annals of clinical and translational neurology, 2015Co-Authors: Christopher S Walker, Lars Edvinsson, Sajedeh Eftekhari, Rebekah L. Bower, Andrea Wilderman, Paul A. Insel, Henry J. Waldvogel, Muhammad A. Jamaluddin, Andrew F. RussoAbstract:The Trigeminovascular System plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal System.
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differentiation of nerve fibers storing cgrp and cgrp receptors in the peripheral Trigeminovascular System
The Journal of Pain, 2013Co-Authors: Sajedeh Eftekhari, Lars Edvinsson, Karin Warfvinge, Frank W BlixtAbstract:Abstract Primary headaches such as migraine are postulated to involve the activation of sensory trigeminal pain neurons that innervate intracranial blood vessels and the dura mater. It is suggested that local activation of these sensory nerves may involve dural mast cells as one factor in local inflammation, causing sensitization of meningeal nociceptors. Immunofluorescence was used to study the detailed distribution of calcitonin gene–related peptide (CGRP) and its receptor components calcitonin receptor–like receptor (CLR) and receptor activity–modifying protein 1 (RAMP1) in whole-mount rat dura mater and in human dural vessels. The relative distributions of CGRP, CLR, and RAMP1 were evaluated with respect to each other and in relationship to mast cells, myelin, substance P, neuronal nitric oxide synthase, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide. CGRP expression was found in thin unmyelinated fibers, whereas CLR and RAMP1 were expressed in thicker myelinated fibers coexpressed with an A-fiber marker. CLR and RAMP1 immunoreactivity colocalized with mast cell tryptase in rodent; however, expression of both receptor components was not observed in human mast cells. Immunoreactive substance P fibers coexpressed CGRP, although neuronal nitric oxide synthase and vasoactive intestinal peptide expression was very limited, and these fibers were distinct from the CGRP-positive fibers. Few pituitary adenylate cyclase-activating polypeptide immunoreactive fibers occurred and some colocalized with CGRP. Perspective This study demonstrates the detailed distribution of CGRP and its receptor in the dura mater. These data suggest that CGRP is expressed in C-fibers and may act on A-fibers, rodent mast cells, and vascular smooth muscle cells that express the CGRP receptor. These sites represent potential pathophysiological targets of novel antimigraine agents such as the newly developed CGRP receptor antagonists.
Karl Messlinger - One of the best experts on this subject based on the ideXlab platform.
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the big cgrp flood sources sinks and signalling sites in the Trigeminovascular System
Journal of Headache and Pain, 2018Co-Authors: Karl MesslingerAbstract:Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the Trigeminovascular System. The available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus. CGRP may be drained off into three different compartments, the venous blood plasma, the cerebrospinal fluid and possibly the glymphatic System. CGRP receptors in peripheral tissues are located on arterial vessel walls, mononuclear immune cells and possibly Schwann cells; within the trigeminal ganglion they are located on neurons and glial cells; in the spinal trigeminal nucleus they can be found on central terminals of trigeminal afferents. All these structures are potential signalling sites for CGRP, where CGRP mediates arterial vasodilatation but not direct activation of trigeminal afferents. In the spinal trigeminal nucleus a facilitating effect on synaptic transmission seems likely. In the trigeminal ganglion CGRP is thought to initiate long-term changes including cross-signalling between neurons and glial cells based on gene expression. In this way, CGRP may upregulate the production of receptor proteins and pro-nociceptive molecules. CGRP and other big molecules cannot easily pass the blood-brain barrier. These molecules may act in the trigeminal ganglion to influence the production of pronociceptive substances and receptors, which are transported along the central terminals into the spinal trigeminal nucleus. In this way peripherally acting therapeutics can have a central antinociceptive effect.
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CGRP and NO in the trigeminal System: mechanisms and role in headache generation.
Headache, 2012Co-Authors: Karl Messlinger, Jochen K Lennerz, Mirjam Eberhardt, Michael J. M. FischerAbstract:Calcitonin gene-related peptide (CGRP) and metabolic products of nitric oxide (NO) are increased in jugular venous plasma during migraine attacks and other primary headaches. Patients suffering from primary headaches are particularly sensitive to CGRP and NO donors responding with delayed headaches to an infusion of either of these substances. Accordingly, both CGRP and NO are considered as key mediators in migraine, and clinical trials have shown that inhibitors of CGRP receptors and NO synthase are effective in treating migraine. There is an implicit understanding that CGRP and NO Systems interact, and here, we review the body of preclinical work on these Systems focusing on the Trigeminovascular System in migraine. NO derives from various cell types via 3 isoforms of NO synthase, whereas CGRP is produced from a subset of trigeminal afferents. In rodents, NO donors cause activity alterations on different levels of the trigeminal System including enhancement of CGRP release, which in turn results in arterial vasodilatation and possibly mast cell degranulation in the meninges. The activity of spinal trigeminal neurons, which is a sensitive integrative measure for trigeminal activity, is partly under the control of CGRP and NO. Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. These functions are supported by immunolocalization of CGRP receptor components on 3 Trigeminovascular levels: cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus. Current data support a relationship of CGRP and NO actions on all levels of the Trigeminovascular System and emphasize central CGRP receptors as possible therapeutic targets.
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Migraine: where and how does the pain originate?
Experimental Brain Research, 2009Co-Authors: Karl MesslingerAbstract:Migraine is a complex neurological disease with a genetic background. Headache is the most prominent and clinically important symptom of migraine but its origin is still enigmatic. Numerous clinical, histochemical, electrophysiological, molecular and genetical approaches form a puzzle of findings that slowly takes shape. The generation of primary headaches like migraine pain seems to be the consequence of multiple pathophysiological changes in meningeal tissues, the trigeminal ganglion, trigeminal brainstem nuclei and descending inhibitory Systems, based on specific characteristics of the Trigeminovascular System. This contribution reviews the current discussion of where and how the migraine pain may originate and outlines the experimental work to answer these questions.
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calcitonin receptor like receptor clr receptor activity modifying protein 1 ramp1 and calcitonin gene related peptide cgrp immunoreactivity in the rat Trigeminovascular System differences between peripheral and central cgrp receptor distribution
The Journal of Comparative Neurology, 2008Co-Authors: Jochen K Lennerz, Victor Ruhle, Eugene P Ceppa, Winfried Neuhuber, Nigel W Bunnett, Eileen F Grady, Karl MesslingerAbstract:Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat Trigeminovascular System we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare (≈0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to “glomerular structures,” partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the Trigeminovascular System CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches. J. Comp. Neurol. 507:1277–1299, 2008. © 2008 Wiley-Liss, Inc.
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Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat Trigeminovascular System: Differences between peripheral and central CGRP receptor distribu
The Journal of Comparative Neurology, 2008Co-Authors: Jochen K Lennerz, Victor Ruhle, Eugene P Ceppa, Winfried Neuhuber, Nigel W Bunnett, Eileen F Grady, Karl MesslingerAbstract:Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat Trigeminovascular System we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare (≈0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to “glomerular structures,” partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the Trigeminovascular System CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches. J. Comp. Neurol. 507:1277–1299, 2008. © 2008 Wiley-Liss, Inc.
Christopher S Walker - One of the best experts on this subject based on the ideXlab platform.
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pituitary adenylate cyclase activating polypeptide receptors in the Trigeminovascular System implications for migraine
British Journal of Pharmacology, 2018Co-Authors: Tahlia Sundrum, Christopher S WalkerAbstract:: The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in a wide range of functions including vasodilatation, neuroprotection, nociception and neurogenic inflammation. PACAP activates three distinct receptors, the PAC1 receptor, which responds to PACAP, and the VPAC1 and VPAC2 receptors, which respond to both PACAP and vasoactive intestinal polypeptide. The Trigeminovascular System plays a key role in migraine and contains the trigeminal nerve, which is the major conduit of craniofacial pain. PACAP is expressed throughout the Trigeminovascular System and in higher brain regions involved in processing pain. Evidence from human clinical studies suggests that PACAP may act outside the blood-brain barrier in the pathogenesis of migraine. However, the precise mechanisms involved remain unclear. PACAP potentially induces migraine attacks by activating different receptors in different cell types and tissues. This complexity prompted this review of PACAP receptor pharmacology, expression and function in the Trigeminovascular System. Current evidence suggests that the PAC1 receptor is the likely pathophysiological target of PACAP in migraine. However, multiple PACAP receptors are expressed in key parts of the Trigeminovascular System and further work is required to determine their contribution to PACAP physiology and the pathology of migraine. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
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pacap receptors in the Trigeminovascular System implications for migraine
British Journal of Pharmacology, 2017Co-Authors: Tahlia Sundrum, Christopher S WalkerAbstract:The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in a wide range of functions including vasodilation, neuroprotection, nociception and neurogenic inflammation. PACAP activates three distinct receptors, the PAC1 receptor, which responds to PACAP and the VPAC1 and VPAC2 receptors, which respond to both PACAP and vasoactive intestinal polypeptide (VIP). The Trigeminovascular System plays a key role in migraine and contains the trigeminal nerve, which is the major conduit of craniofacial pain. PACAP is expressed throughout the Trigeminovascular System and in higher brain regions involved in processing pain. Evidence from human clinical studies suggests that PACAP may act outside the blood brain barrier in the pathogenesis of migraine. However, the precise the mechanisms involved remain unclear. PACAP potentially induces migraine attacks by activating different receptors in different cell types and tissues. This complexity prompted this review of PACAP receptor pharmacology, expression and function in the Trigeminovascular System. Current evidence suggests that the PAC1 receptor is the likely pathophysiological target of PACAP in migraine. However, multiple PACAP receptors are expressed in key parts of the Trigeminovascular System and further work is required to determine their contribution to PACAP physiology and the pathology of migraine.
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CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.
Cephalalgia, 2017Co-Authors: Christopher S Walker, Ann C Raddant, Michael J. Woolley, Andrew F. RussoAbstract:BackgroundCalcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the Trigeminovascular System and is believed to play an important role in migraine. CGRP activates two receptors that...
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A second trigeminal CGRP receptor: function and expression of the AMY1 receptor
Annals of clinical and translational neurology, 2015Co-Authors: Christopher S Walker, Lars Edvinsson, Sajedeh Eftekhari, Rebekah L. Bower, Andrea Wilderman, Paul A. Insel, Henry J. Waldvogel, Muhammad A. Jamaluddin, Andrew F. RussoAbstract:The Trigeminovascular System plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal System.
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cgrp in the Trigeminovascular System a role for cgrp adrenomedullin and amylin receptors
British Journal of Pharmacology, 2013Co-Authors: Christopher S WalkerAbstract:The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the Trigeminovascular System. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the Trigeminovascular System. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this System and that further work is required to determine their contribution to CGRP physiology and pathophysiology. LINKED ARTICLES This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7
Jochen K Lennerz - One of the best experts on this subject based on the ideXlab platform.
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CGRP and NO in the trigeminal System: mechanisms and role in headache generation.
Headache, 2012Co-Authors: Karl Messlinger, Jochen K Lennerz, Mirjam Eberhardt, Michael J. M. FischerAbstract:Calcitonin gene-related peptide (CGRP) and metabolic products of nitric oxide (NO) are increased in jugular venous plasma during migraine attacks and other primary headaches. Patients suffering from primary headaches are particularly sensitive to CGRP and NO donors responding with delayed headaches to an infusion of either of these substances. Accordingly, both CGRP and NO are considered as key mediators in migraine, and clinical trials have shown that inhibitors of CGRP receptors and NO synthase are effective in treating migraine. There is an implicit understanding that CGRP and NO Systems interact, and here, we review the body of preclinical work on these Systems focusing on the Trigeminovascular System in migraine. NO derives from various cell types via 3 isoforms of NO synthase, whereas CGRP is produced from a subset of trigeminal afferents. In rodents, NO donors cause activity alterations on different levels of the trigeminal System including enhancement of CGRP release, which in turn results in arterial vasodilatation and possibly mast cell degranulation in the meninges. The activity of spinal trigeminal neurons, which is a sensitive integrative measure for trigeminal activity, is partly under the control of CGRP and NO. Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. These functions are supported by immunolocalization of CGRP receptor components on 3 Trigeminovascular levels: cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus. Current data support a relationship of CGRP and NO actions on all levels of the Trigeminovascular System and emphasize central CGRP receptors as possible therapeutic targets.
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calcitonin receptor like receptor clr receptor activity modifying protein 1 ramp1 and calcitonin gene related peptide cgrp immunoreactivity in the rat Trigeminovascular System differences between peripheral and central cgrp receptor distribution
The Journal of Comparative Neurology, 2008Co-Authors: Jochen K Lennerz, Victor Ruhle, Eugene P Ceppa, Winfried Neuhuber, Nigel W Bunnett, Eileen F Grady, Karl MesslingerAbstract:Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat Trigeminovascular System we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare (≈0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to “glomerular structures,” partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the Trigeminovascular System CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches. J. Comp. Neurol. 507:1277–1299, 2008. © 2008 Wiley-Liss, Inc.
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Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat Trigeminovascular System: Differences between peripheral and central CGRP receptor distribu
The Journal of Comparative Neurology, 2008Co-Authors: Jochen K Lennerz, Victor Ruhle, Eugene P Ceppa, Winfried Neuhuber, Nigel W Bunnett, Eileen F Grady, Karl MesslingerAbstract:Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat Trigeminovascular System we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare (≈0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to “glomerular structures,” partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the Trigeminovascular System CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches. J. Comp. Neurol. 507:1277–1299, 2008. © 2008 Wiley-Liss, Inc.
