Headaches that accompany intracranial pathologies as well as the headache of migraine are thought to result from mechanically or chemically induced activation or sensitization of sensory nerve fibers in the intracranial meninges. However, further understanding of the mechanisms of headaches is limited by the lack of information regarding the response properties of meningeal sensory fibers. The long-term goal of this research is to identify the types of stimuli and physiological conditions that excite meningeal primary afferent neurons and to investigate the pharmacological mechanisms by which their excitation may be suppressed.
Five Specific Aims are proposed to examine the responses of both pial and dural afferents.
Specific Aim 1 will characterize the physiological response properties of sensory afferents supplying the middle cerebral artery using graded mechanical and chemical stimuli.
Specific Aim 2 will determine the effects of increased intracranial pressure and inflammation on the response properties of meningeal afferents that innervate the dural venous sinuses and middle cerebral artery.
Specific Aim 3 will determine the effects of 5HT1B/D agonists on mechanical- and chemical-induced sensitized meningeal afferents.
Specific Aim 4 will determine the effects of selective calcium channel blockers on mechanical- and chemical-induced sensitized meningeal afferents.
Specific Aim 5 will determine the effects of acute spreading depression on mechanical- and chemical-induced sensitized meningeal afferents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032534-08
Application #
6639454
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Porter, Linda L
Project Start
1996-05-01
Project End
2005-01-14
Budget Start
2003-04-01
Budget End
2005-01-14
Support Year
8
Fiscal Year
2003
Total Cost
$236,333
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, XiChun; Kainz, Vanessa; Zhao, Jun et al. (2013) Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol 73:741-50
Levy, Dan; Kainz, Vanessa; Burstein, Rami et al. (2012) Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity. Brain Behav Immun 26:311-7
Zhang, Xi-Chun; Kainz, Vanessa; Jakubowski, Moshe et al. (2009) Localization of COX-1 and COX-2 in the intracranial dura mater of the rat. Neurosci Lett 452:33-6
Zhang, X-C; Levy, D (2008) Modulation of meningeal nociceptors mechanosensitivity by peripheral proteinase-activated receptor-2: the role of mast cells. Cephalalgia 28:276-84
Levy, Dan; Burstein, Rami; Kainz, Vanessa et al. (2007) Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 130:166-76
Zhang, Xi-Chun; Strassman, Andrew M; Burstein, Rami et al. (2007) Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther 322:806-12
Strassman, Andrew M; Levy, Dan (2006) Response properties of dural nociceptors in relation to headache. J Neurophysiol 95:1298-306
Levy, Dan; Burstein, Rami; Strassman, Andrew M (2005) Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58:698-705
Strassman, Andrew M; Levy, Dan (2004) The anti-migraine agent sumatriptan induces a calcium-dependent discharge in meningeal sensory neurons. Neuroreport 15:1409-12
Strassman, Andrew M; Weissner, Wendi; Williams, Molly et al. (2004) Axon diameters and intradural trajectories of the dural innervation in the rat. J Comp Neurol 473:364-76

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