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Headache
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Until recently, the choice of preventive agent was primarily determined by the patient, and which potential adverse effects are most acceptable since they are common are given in Table 6.5. The advent of CGRP pathway monoclonal antibodies has substantially changed the clinical approach where they are available.37 Discussion of the adverse effect profile of each drug with the patient can be a very effective way to determine their preference and enhance compliance. Asthma (beta-blockers), weight gain (pizotifen and valproate), and cognitive dysfunction (topiramate) are major and common concerns. Botulinum toxin type A has been licensed in many countries specifically to treat chronic (≥15 days a month) migraine (Table 6.5).38
Proinflammatory Peptides in Sensory Nerves of the Airways
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Peter Baluk, Donald M. McDonald
CGRP is a 37-amino acid peptide that results from alternative splicing of the mRNA of the precursor coded by the calcitonin gene. Human CGRP has at least two isoforms, termed CGRPα and CGRPβ, that differ by three amino acids, with other slight differences in other species. Both isoforms are present in peripheral sensory neurons (157). The molecular biology and pharmacology of CGRP has been reviewed elsewhere (18,158,159). CGRP is co-localized with tachykinins in sensory nerves (40,46), and is present in the airways of several species, including humans. In fact, in some cases CGRP appears to be present in a greater number of sensory nerves than substance P, and is detected in greater amounts biochemically (160). This property may be due partly to the greater resistance of CGRP than substance P to enzymatic degradation (161), and makes CGRP a useful assay of sensory nerve peptide release (160,162). In some species, especially rodents, CGRP is also present in airway neuroendocrine cells (34,42,44) (Fig. 2E). In rats, CGRP is also located in some serous-type epithelial cells (44).
Putative Mediators in Inflammatory Bowel Disease: Substance P and Calcitonin Gene-Related Peptide.
Published in William J. Snape, Stephen M. Collins, Effects of Immune Cells and Inflammation on Smooth Muscle and Enteric Nerves, 2020
Viktor E. Eysselein, Catia Sternini, Fabio Cominelli, Cynthia C. Nast
CGRP, which is the most potent vasoactive peptide described to date47, may also be involved in inflammatory reactions of several tissues. CGRP increases blood flow by a direct action on arterial smooth muscles and causes in the skin a long-lasting, delayed-onset erythema.5 In the skin, CGPR potentiates the edema induced by substance P, histamine, bradykinin, platelet activating factor and leukotriene B4.5,27 These findings would support the concept that CGRP enhances the inflammatory response.
Communication between the gut microbiota and peripheral nervous system in health and chronic disease
Published in Gut Microbes, 2022
Tyler M. Cook, Virginie Mansuy-Aubert
Along with immune cells, enteric, spinal, and vagal neurons express toll-like receptors (TLRs). Disrupted TLR signaling in peripheral neurons may contribute to deficits in enteric nervous development, gut motility, immunity, and visceral perception (Figure 4). LPS binds to toll-like receptor 4 (TLR4) and LTA binds TLR2. TLR2 expressed in spinal sensory neurons and activation can alter the reflex release of neuropeptides capable of increasing cytokines.67 TLR4 is expressed in vagal neurons which play a key role in the inflammatory reflex where the brain senses potential proinflammatory signals and regulates the immune responses.67,68 This is accomplished by vagal efferent release of acetylcholine onto immune cells in target tissues which can dampen the local immune response. Additionally, vagal TLR4 signaling mediates LPS-induced release of the neuropeptide calcitonin gene-regulated peptide (CGRP).69 CGRP is a vasodilatory neuropeptide released by spinal and vagal afferent neurons, as well as enteric neurons, which contributes to inflammation resolution and pain.70
A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications
Published in Expert Review of Neurotherapeutics, 2021
Bruno A. Marichal-Cancino, Abimael González-Hernández, Raquel Guerrero-Alba, Roberto Medina-Santillán, Carlos M. Villalón
Although all gepants block the CGRPergic transmission, none of these molecules seems to produce cardiovascular side effects when given acutely [200,216]. For example, a supratherapeutic dosage of telcagepant (a first-generation gepant) in healthy volunteers did not affect vascular tone in peripheral and central vascular beds [217]. Nevertheless, as pointed out above, CGRP may play a protective role during pathological conditions. Within this context: (i) Mulder et al. [218] have shown in a surrogate model of stroke in mice that olcegepant and rimegepant worsened the ischemic outcome by occlusion of the middle cerebral artery [218]; and (ii) Rubio-Beltrán et al. [219] demonstrated in vitro that atogepant and ubrogepant blocked the CGRP-induced vasorelaxation of human intracranial arteries without vasoconstrictor effects on human coronary arteries. These data imply that: (i) during a migraine attack, where CGRP is released from perivascular trigeminal fibers, gepants blocked CGRP-induced vasodilation; and (ii) these compounds produced no effects in the coronary circulation (at least during acute exposure). Hence, long-term safety studies with atogepant will shed light on the relevance of perivascular CGRPergic transmission.
A rational approach to migraine diagnosis and management in primary care
Published in Annals of Medicine, 2021
Vincent T. Martin, Alexander Feoktistov, Glen D. Solomon
CGRP levels were found to be elevated in patient blood, saliva, and cerebrospinal fluid samples during migraine attacks [36]. Follow-up studies showed that intravenous infusion of CGRP triggers migraine-like headaches preferentially in patients with migraine compared to healthy controls, supporting the notion that CGRP may play an important role in migraine pathogenesis [36]. Although the precise function of CGRP during migraine is unknown, CGRP and its receptor are expressed at sites throughout the CNS, as shown in Figure 3, some of which have been linked to migraine symptoms, including pain processing, nausea, photophobia, and phonophobia [36]. Further evidence for the pivotal role of CGRP in migraine comes from clinical trial data showing that multiple pharmacotherapeutics that block the CGRP pathway can effectively manage migraine [36].