Migraine pain, meningeal inflammation, and mast cells
ABSTRACT Migraine pain has been attributed to an episode of local sterile meningeal inflammation and the subsequent activation of trigeminal primary afferent nociceptive neurons that supply the intracranial meninges and their related large blood vessels. However, the origin of this inflammatory insult and the endogenous factors that contribute to the activation of meningeal nociceptors remain largely speculative. A particular class of inflammatory cells residing within the intracranial milieu, known as meningeal mast cells, was suggested to play a role in migraine pathophysiology more than five decades ago, but until recently the exact nature of their involvement remained largely unexplored. This review examines the evidence linking meningeal mast cells to migraine and highlights current experimental data implicating these immune cells as potent modulators of meningeal nociceptors' activity and the genesis of migraine pain.
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ABSTRACT: Inflammatory mediators, including adipokines, have been studied in migraine pathophysiology; however, their role is not yet well established. The aim of the present study was to investigate adiponectin (ADP) and its association with clinical parameters and psychiatric comorbidities in migraine patients compared with controls. This was a cross sectional study including migraine patients and controls. Beck depression and anxiety inventories, Headache impact test, and Allodynia symptom checklist were recorded. Adiponectin was measured by ELISA. Sixty-eight migraine patients and sixty-five controls without headache were included. The ADP levels were significantly higher among patients with migraine (43.6±11.8 versus 36.6±9.7ng/mL, P<0.0001). Adiponectin levels were not correlated with depression and anxiety scores, as well as with migraine severity and allodynia scores. ADP levels were raised in migraine, independently of psychiatric comorbidities, migraine impact, and allodynia.Journal of the neurological sciences 04/2014; 342(1-2). DOI:10.1016/j.jns.2014.04.035 · 2.26 Impact Factor
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ABSTRACT: Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFα, lymphotoxin α (LTA), and lymphotoxin β (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFα contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine.Twin Research and Human Genetics 09/2013; 16(6):1-8. DOI:10.1017/thg.2013.63 · 1.92 Impact Factor
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ABSTRACT: Background and Purpose: Calcitonin gene-related peptide (CGRP) is a potent vasodilator, implicated in the pathogenesis of migraine. CGRP activates a receptor complex comprising, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). In vitro studies indicate recycling of CLR•RAMP1 is regulated by degradation of CGRP in early endosomes by endothelin-converting enzyme-1 (ECE-1). However, it is not known if ECE-1 regulates the resensitization of CGRP-induced responses in functional arterial tissue. Experimental Approach: CLR, ECE-1a-d and RAMP1 expression in rat mesenteric artery smooth muscle cells (RMA-SMCs) and mesenteric arteries was analyzed by RT-PCR and by immunofluorescence and confocal microscopy. CGRP-induced signaling in cells was examined by measuring cAMP production and ERK activation. CGRP-induced relaxation of arteries was measured by isometric wire myography. ECE-1 was inhibited using the specific inhibitor, SM-19712. Key Results: RMA-SMCs and arteries contained mRNA for CLR, ECE-1a-d and RAMP1. ECE-1 was present in early endosomes of RMA-SMCs and in the smooth muscle layer of arteries. CGRP induced endothelium-independent relaxation of arteries. ECE-1 inhibition had no effect on initial CGRP-induced responses but reduced cAMP generation in RMA-SMCs and vasodilation in mesenteric arteries responses to subsequent CGRP challenges. Conclusions and Implications: ECE-1 regulates the resensitization of responses to CGRP in RMA-SMCs and mesenteric arteries. CGRP-induced relaxation does not involve endothelium-derived pathways. This is the first report of ECE-1 regulating CGRP responses in SMCs and arteries. ECE-1 inhibitors may attenuate an important vasodilatory pathway, implicated in primary headaches and may represent a new therapeutic approach for the treatment of migraine. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.British Journal of Pharmacology 08/2012; 167(8). DOI:10.1111/j.1476-5381.2012.02129.x · 4.99 Impact Factor