Headaches of intracranial origin have been suggested to result from the activation of primary afferent nociceptive neurons innervating intracranial blood vessels and the meninges. Endogenous factors underlying this neuronal activation remain poorly understood. Mast cells were implicated in numerous chronic painful conditions, including intracranial headaches. Given the ability of mast cells to release an abundance of algesic mediators and their proximity to nociceptors, a functional relationship is suggested. However, a direct link between mast cell activation, release of mediators and enhanced nociceptor excitability leading to activation of nociceptive pathways remained unexplored. Based on our preliminary data we hypothesized that dural mast cell degranulation, release of mediators and subsequent leukocyte recruitment promote activation of intracranial dural nociceptors, enhance their mechanosensitivity, and induce activation of dorsal horn neurons that process intracranial nociceptive input. We propose to use a multidisciplinary approach including electrophysiological, pharmacological, histological, and immunocytochemical methods to test our hypothesis.
Three specific aims are proposed.
In specific aim 1, single-unit recording of dural nociceptors from the trigeminal ganglion will be used to determine whether mast cell degranulation promotes activation and mechanical sensitization of dural nociceptors.
In specific Aim 2, using both electrophysiological single unit recording, and c-fos expression as a marker of nociceptive neuronal activation, we will determine whether dural mast cell degranulation is sufficient to promote activation/sensitization of trigeminovascular dorsal horn neurons.
In specific aim 3, single-unit recording combined with a pharmacological approach will be used to examine the relative contribution of the mast cell mediators; nitric oxide, TNF-alpha and tryptase and the role of leukocyte recruitment to dural mast cell-induced nociceptor activation and mechanical sensitization. Data obtained in these studies could provide a better understanding on the link between mast cells and deep tissue nociceptors, especially those innervating the intracranial meninges. Results may help identify pharmacological targets that could lead to the development of novel analgesic drugs for the treatment of headaches and possibly other intractable pain syndromes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046502-03
Application #
7037611
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$230,331
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Zhang, Xichun; Burstein, Rami; Levy, Dan (2012) Local action of the proinflammatory cytokines IL-1? and IL-6 on intracranial meningeal nociceptors. Cephalalgia 32:66-72
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; Burstein, Rami et al. (2011) Tumor necrosis factor-* induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain 152:140-9
Levy, Dan (2010) Migraine pain and nociceptor activation--where do we stand? Headache 50:909-16
Zhang, Xichun; Levy, Dan; Noseda, Rodrigo et al. (2010) Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci 30:8807-14
Levy, Dan (2009) Migraine pain, meningeal inflammation, and mast cells. Curr Pain Headache Rep 13:237-40
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; Zhang, Xi-Chun; Jakubowski, Moshe et al. (2008) Sensitization of meningeal nociceptors: inhibition by naproxen. Eur J Neurosci 27:917-22

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