Review Article Cephalalgia 0(0) 1–17 ! International Headache Society 2018 Current understanding of meningeal Reprints and permissions: sagepub.co.uk/journalsPermissions.nav and cerebral vascular function DOI: 10.1177/0333102418771350 underlying migraine headache journals.sagepub.com/home/cep Dan Levy1,2 , Alejandro Labastida-Ramirez3 and Antoinette MaassenVanDenBrink3 Abstract Background: The exact mechanisms underlying the onset of a migraine attack are not completely understood. It is, however, now well accepted that the onset of the excruciating throbbing headache of migraine is mediated by the activation and increased mechanosensitivity (i.e. sensitization) of trigeminal nociceptive afferents that innervate the cranial meninges and their related large blood vessels. Objectives: To provide a critical summary of current understanding of the role that the cranial meninges, their associated vasculature, and immune cells play in meningeal nociception and the ensuing migraine headache. Methods: We discuss the anatomy of the cranial meninges, their associated vasculature, innervation and immune cell population. We then debate the meningeal neurogenic inflammation hypothesis of migraine and its putative contribution to migraine pain. Finally, we provide insights into potential sources of meningeal inflammation and nociception beyond neurogenic inflammation, and their potential contribution to migraine headache. Keywords Meninges, afferent, vascular, immune, neurogenic inflammation Date received: 21 November 2017; revised: 6 March 2018; 19 March 2018; accepted: 26 March 2018 Migraine is a complex, multifactorial neurological disor- a thick layer of connective tissue apposing to the cra- der affecting about 10% of the adult population world- nium, and the leptomeninges. The latter can be further wide (1). It is the second most prevalent neurological separated into the arachnoid and pia mater. The dura disorder (1) and the first cause of disability in under mater can be divided anatomically into three layers, the 50s (2,3). While the exact mechanisms underlying the endosteal (periosteal) layer, the inner meningeal layer, onset of a migraine attack remain unclear, it is now and the dural border cell layer, or subdural neurothe- accepted that the development of the excruciating throb- lium (8). The dural layers are fused in most places, but bing headache of migraine requires the initial activation separate to form the venous sinuses and at the Falx and increased mechanosensitivity (i.e. sensitization) of cerebri. The dural border cell layer is attached to the trigeminal nociceptive afferents that innervate the cranial outer layer of the arachnoid – the arachnoid barrier cell meninges and their related large blood vessels (4–7). The goal of this review is to summarize current knowledge and understanding of the role that the cranial meninges 1Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel and their related vasculature and cellular constituents Deaconess Medical Center, Boston, MA, USA 2Harvard Medical School, Boston, MA, USA play in the meningeal nociceptive processes underlying 3Department of Internal Medicine, Division of Vascular Medicine and the onset of migraine headache. Pharmacology, Erasmus University Medical Center, Rotterdam, The Netherlands (i) Anatomical features of the cranial meninges and their associated vasculature Corresponding author: Dan Levy, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 The cranial meninges are comprised of two main Brookline, DA717, Boston, MA 02215, USA. distinct layers: The dura mater, or pachymeninx, Email: [email protected] 2 Cephalalgia 0(0) layer – by occasional cell junctions, or desmosomes. space, which is filled with cerebrospinal fluid (CSF). Under various pathological conditions, such as in the The pia mater, the most inner meningeal layer, abuts case of subdural hematoma, damage to the dural a cortical barrier layer made of astrocyte endfoot pro- border cell layer can lead to separation of the dura cesses (i.e. the glia limitans, Figure 1(a)). Blood vessels from the arachnoid and the formation of a ‘‘subdural within the subarachnoid space are coated by a pia space’’ (8). The arachnoid layer connects to the thin pia mater layer (hence the name pial vessels). As arteries mater via collagen trabeculae to form the subarachnoid penetrate the brain, a single-layered sheath of pial cells (a) (b) Dura mater Sympathetic Parasympathetic Trigeminal ? NA PACAP ACh CGRP ATP NPY SP NO VIP PACAP Dura mater Arachnoid ? Fibroblast Subarachnoid Dendritic Mast Macrophage Artery Vein Lymphatic space cell cell (CSF) NA ATP PACAP CGRP PACAP NO NA Prostaglandins NPY ACh CGRP VIP PACAP SP NO CLR/RAMP1 PAC/VPAP-R GC/cGMP abPG IP EP TP ATP 5-HT Histamine ACh NGF BDNF TNF-a IL-1 IL-6 K+ Pia mater NO Glutamate 5-HT-R H-R mACh-R nACh-R NGF-R BDNF-R TNF-R IL-1R IL-6R ATP ET ATP SP NPY VIP Astrocyte P2X TRPM8 TRPV1 TRPA1 ET-R P2Y NK1 NPY-R VIP-R Pyramidal Cerebral cortex neuron Dura mater Subarachnoid space (CSF) Arachnoid Arachnoid trabeculae Pia mater Falx cerebri Figure 1. Overview of the cranial meninges and their associated constituents. (a) Schematic illustration of meningeal innervation components in relation to superficial cortical constituents and their mediators (red and yellow, denoting molecules released from neurons and astrocytes respectively), which upon reaching the subarachnoid space via diffusion or bulk flow, could underlie the cortical to meninges signaling in migraine with aura and perhaps also in migraine without aura. (b) Postulated crosstalk between meningeal autonomic and sensory nerves, resident immune cells, fibroblasts and vessels that have been suggested to contribute to meningeal nociception and headache and receptor systems that have been (i) implicated in the genesis of migraine pain in clinical studies (black font), (ii) suggested to activate and/or sensitize the meningeal sensory system based on preclinical studies (blue font), or with questionable contribution to meningeal nociception and headache pain (red font). CGRP: calcitonin gene-related peptide; PACAP: pituitary adenylate cyclase-activating polypeptide; NO: nitric oxide; NA: noradrena- line; ACh: acetylcholine; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; TNF-a: tumor necrosis factor; IL-1: interleukin-1; IL-6: interleukin 6; ATP: adenosine triphosphate; SP: substance P; NPY: neuropeptide Y; VIP: vasoactive intestinal peptide; ET: endothelin. Levy et al. 3 is maintained for a short distance and separates to suggest expression of glutamate in meningeal affer- between the vessel wall and the glia limitans (9,10). ents, a recent retrograde tracing study in the mouse Upon entering the cortex, the pial layer that surrounds identified vesicular glutamate transporter 3 in a subpo- the arterioles becomes fenestrated. Penetrating veins pulation of small diameter dural afferents (26). lack a continuous pial layer (9). The dura mater is also innervated by The dura mater is highly vascularized. The arterial autonomic fibers that express PACAP, neuronal nitric supply of the supratentorial dura mater comes primar- oxide synthase (nNOS), vasoactive intestinal polypep- ily from branches of the posterior, middle (the largest), tide (VIP), tyrosine hydroxylase (TH), acetylcholine and anterior meningeal arteries, which arise from (ACh), and neuropeptide Y (NPY) (18,21–24,27–31). the occipital, maxillary, and ophthalmic arteries respec- Ultrastructural studies conducted in the rat localized tively. Meningeal arteries lie predominantly in the some peptidergic fibers’ termination in the vicinity, or endosteal layer. The intracranial middle meningeal walls, of dural blood vessels including lymphatics; artery, which enters the cranium through the foramen axon terminations on collagen bundles in the dural spinosum, runs in grooves in the inner table of the connective tissue have been shown to be more abun- calvarium, surrounded almost on three sides by bone dant, however (12,18). Within the leptomeningeal, (11). A dense capillary network occurs in the inner which lack their own blood supply, the cerebral (pial) meningeal layer of the dura. The major dural veins, arteries are the primary sites that receive sensory and which run primarily parallel to the path of the menin- autonomic innervations by fibers that originate from geal arteries, drain into efferent vessels in the periosteal sympathetic, parasympathetic, and sensory trigeminal layer or the dural venous sinuses. The dural venous ganglia (Figure 1(a)). Immunohistochemistry studies sinuses absorb CSF from the subarachnoid space via together with denervation and tracing studies identified arachnoid granulations. Studies in rodents also identi- trigeminal nerves expressing substance P and CGRP, as fied a dural lymphatic vascular network alongside well as autonomic nerves that express NPY, VIP, blood vessels, primarily the middle meningeal artery, nNOS, ACh, and tryptophan-5-hydroxylase (28,32– superior sagittal sinus, and transverse sinuses (12–15). 39). The sensory and autonomic innervation of cerebral A recent study in non-human primates and humans pial vessels is primarily localized to the subarachnoid has shown that the dural lymphatic system drains space and does not follow the vessels when they macromolecules from the dura (15). In rodents, dural penetrate the cortex; the loss of pial sheath in the pene- lymphatics drain CSF and parenchymal interstitial fluid trating