Sensitization and Activation of Intracranial Meningeal Nociceptors by Mast Cell Mediators

Harvard University, Cambridge, Massachusetts, United States
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/2007; 322(2):806-12. DOI: 10.1124/jpet.107.123745
Source: PubMed


Intracranial headaches such as migraine are thought to result from activation of sensory trigeminal pain neurons that supply intracranial blood vessels and the meninges, also known as meningeal nociceptors. Although the mechanism underlying the triggering of such activation is not completely understood, our previous work indicates that the local activation of the inflammatory dural mast cells can provoke a persistent sensitization of meningeal nociceptors. Given the potential importance of mast cells to the pain of migraine it is important to understand which mast cell-derived mediators interact with meningeal nociceptors to promote their activation and sensitization. In the present study, we have used in vivo electrophysiological single-unit recording of meningeal nociceptors in the trigeminal ganglion of anesthetized rats to examine the effect of a number of mast cell mediators on the activity level and mechanosensitivity of meningeal nociceptors. We have found that that serotonin (5-HT), prostaglandin I(2) (PGI(2)), and to a lesser extent histamine can promote a robust sensitization and activation of meningeal nociceptors, whereas the inflammatory eicosanoids PGD(2) and leukotriene C(4) are largely ineffective. We propose that dural mast cells could promote headache by releasing 5-HT, PGI(2), and histamine.

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    • "Indeed, the pathophysiology of conditions such as migraine has been long associated with impaired functionality of dura mater microvasculature (including altered microvessel permeability) as well as sex hormone imbalances. The increase in vascular permeability [21], [22] and vasodilation of meningeal arterioles [23] induced by mast cell mediators have been suggested as putative mechanisms underlying vascular headaches such as migraine [24]. Further, recent studies demonstrate that migraine-associated recruitment and maturation of dura mater mast cells, usually located perivascularly [25], also critically depend on ovarian hormone production [26]. "
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    ABSTRACT: In postmenopausal women, estrogen (E2) deficiencies are frequently associated with higher risk of intracranial hemorrhage, increased incidence of stroke, cerebral aneurysm, and decline in cognitive abilities. In younger postpartum women and those using oral contraceptives, perturbations in E2 are associated with higher risk of cerebral venous thrombosis. A number of serious intracranial pathologic conditions linked to E2 deficiencies, such as dural sinus thrombosis, dural fistulae, non-parenchymal intracranial hemorrhages, migraines, and spontaneous cerebrospinal fluid leaks, involve the vessels not of the brain itself, but of the outer fibrous membrane of the brain, the dura mater (DM). The pathogenesis of these disorders remains mysterious and how estrogen regulates structural and functional integrity of DM vasculature is largely unknown. Here, we demonstrate that post ovariectomy (OVX) DM vascular remodeling is manifested by microvessel destabilization, capillary rarefaction, increased vascular permeability, and aberrant angio-architecture, and is the result of disrupted E2-regulated PDGF-BB signaling within dura microvasculature. These changes, associated with the reduction in systemic PDGF-BB levels, are not corrected by a flat-dose E2 hormone replacement therapy (HRT), but are largely prevented using HRT schedules mimicking physiological E2 fluctuations. We demonstrate that 1) E2 regulates PDGF-BB production by endothelial cells in a dose-dependent manner and 2) optimization of PDGF-BB levels and induction of robust PDGF-mediated endothelial cell-vascular pericyte interactions require high (estrous) E2 concentrations. We conclude that high (estrous) levels of E2 are important in controlling PDGF-mediated crosstalk between endothelial cells and pericytes, a fundamental mechanism governing microvessel stability and essential for preserving intracranial homeostasis.
    PLoS ONE 12/2013; 8(12):e82900. DOI:10.1371/journal.pone.0082900 · 3.23 Impact Factor
    • "activated following trigeminal nerve activation, cervical or sphenopalatine ganglion stimulation (Edvinsson et al., 1976; Levy 2009; Levy et al., 2007; Ottosson and Edvinsson, 1997; Rozniecki et al., 1999; Theoharides et al., 2005; Zhang et al., 2007). PACAP acts via G protein-coupled receptors mainly associated with the adenylate cyclase and phospholipase C signal transduction pathways: the pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1) specifically binding PACAP, and the vasoactive intestinal polypeptide receptor 1 (VPAC1) and vasoactive intestinal polypeptide receptor 2 (VPAC2) having a similar binding affinity for PACAP and VIP. "
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    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC) are present in sensory neurons and vascular smooth muscle. PACAP infusion was found to trigger migraine-like headache in humans and we showed its central pro-nociceptive function in several mouse pain models. Nitroglycerol (NTG)-induced pathophysiological changes were investigated in this study in PACAP gene-deleted (PACAP(-/-)) and wildtype (PACAP(+/+)) mice. Chemical activation of the trigeminovascular system was induced by 10 mg/kg i.p. NTG. Light-aversive behavior was determined in a light-dark box, meningeal microcirculation by laser Doppler blood perfusion scanning and the early neuronal activation marker c-Fos with immunohistochemistry. NTG-induced photophobia both in the early (0-30 min) and late phases (90-120 min) due to direct vasodilation and trigeminal sensitization, respectively, was significantly reduced in PACAP(-/-) mice. Meningeal blood flow increased by 30-35% during 4 h in PACAP(+/+) mice, but only a 5-10% elevation occurred from the second hour in PACAP(-/-) ones. The number of c-Fos expressing cells referring to neuronal activation in the trigeminal ganglia and nucleus caudalis significantly increased 4h after NTG in PACAP(+/+), but not in PACAP(-/-) animals. Similar PAC1 receptor immunostaining was detected in both groups, which did not change 4 h after NTG treatment. PACAP-38 (300 μg/kg, i.p.) produced photophobia similarly to NTG and 30% meningeal vasodilatation for 30 min in PACAP(+/+), but not in PACAP(-/-) mice. It significantly increased neural activation 4h later in the trigeminal ganglia of both groups, but in the nucleus caudalis of only the PACAP(+/+) mice. We provide the first experimental results that PACAP is a pivotal mediator of trigeminovascular activation/sensitization and meningeal vasodilation related to migraine.
    Neurobiology of Disease 01/2012; 45(1):633-44. DOI:10.1016/j.nbd.2011.10.010 · 5.08 Impact Factor
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    • "Since little to no white matter separates the lumbar dorsal horn from the subarachnoid and dura mater, it is hypothesized that mediators released from dura mast cells can reach the superficial laminae, a key relay station for nociception [19], to modulate synaptic transmission and nociception. While some of the individual mast cell mediators also produced by other immune cells are implicated in nociception and spinal synaptic transmission [20-22], the combination of mediators some of which serve anti-inflammatory and homeostatic functions [1], has not been specifically studied. To examine this, mast cells were cultured and activated in vitro and the mast cell supernatant was injected intrathecally to assess nociception. "
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    ABSTRACT: Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation. Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP) at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk) inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia. The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.
    Molecular Pain 06/2011; 7(1):42. DOI:10.1186/1744-8069-7-42 · 3.65 Impact Factor
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