Persistent headache is one of the most common symptoms following a mild traumatic head injury, but for many individuals with posttraumatic headache (PTH) overall pain management remains unsatisfactory, leading to suffering and poor quality of life. The inability to effectively control PTH pain can be attributed in part to the poo understanding of the pathophysiology underlying PTH. Preclinical research on PTH has been hampered by the lack of an animal model that mimics the most common type of head trauma and exhibits behaviors that can be linked to ongoing headache and persistent pain. The goal of following proposal is to examine key peripheral mechanisms that could contribute to the development of PTH pain. Based on exciting preliminary data, our working hypothesis is that mild head trauma leads to inflammatory-driven persistent activation and sensitization of primary afferent neurons that innervate the extracranial calvarial periosteum and intracranial dura mater, which in turn promote the development of sensory and affective changes that can be linked to PTH pain. We propose a series of studies that employ electrophysiology, behavioral testing, histology, pharmacology and mutant animals that lack immune cells to study our working hypothesis by addressing the following open questions: 1) Does head trauma lead to persistent activation and increased mechanical and chemical sensitivities of primary afferent neurons that innervate the calvarial periosteum and/or intracranial dura (Specific Aim 1)? 2) If so, do these neurophysiological changes correlate and contribute to the development of pericranial cutaneous allodynia, a sensory change linked to persistent headache, and suppression of burrowing, a change in innate behavior that reflects an affective (aversive) dimension of persistent pain (Specific Aim 2)? 3) Does a posttraumatic peripheral inflammatory response, in particular the recruitment and activation of immune cells within the skull's periosteum and intracranial dura, contribute to the posttraumatic neurophysiological changes and the ensuing behavioral changes linked to PTH pain. Results from this project will provide important insights into the pathogenesis of PTH, including the peripheral tissues from which PTH pain likely arise, the neurophysiological correlate of the headache and its underlying mechanisms. This novel information could lead to the expansion of the targets of interventions that can be used to alleviate this poorly understood trauma-related pain.

Public Health Relevance

Posttraumatic headache affects the lives of many Americans, including soldiers and veterans but its underlying pathophysiology remains obscure. The proposed study will provide important information about the peripheral mechanisms underlying this trauma-related persistent pain, including insights into the extracranial and intracranial loci responsible for the development of the headache, its neurophysiological correlate and underlying cellular mechanisms. A better understanding of these mechanisms could shed light on this poorly understood condition and contribute essential information to assist in the development of much needed evidence-based therapies to conquer the headache.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS086830-01A1
Application #
8814839
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Hicks, Ramona R
Project Start
2014-08-15
Project End
2019-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$380,625
Indirect Cost
$161,875
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Levy, Dan; Abdian, Lorin; Dekel-Steinkeller, Michal et al. (2018) Experimental evidence for weaker endogenous inhibition of trigeminal pain than extra-trigeminal pain in healthy individuals. Cephalalgia 38:1307-1315
Zhao, Jun; Levy, Dan (2018) Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. J Neurosci 38:5053-5066
Bree, Dara; Levy, Dan (2018) Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 38:246-258
Levy, Dan; Labastida-Ramirez, Alejandro; MaassenVanDenBrink, Antoinette (2018) Current understanding of meningeal and cerebral vascular function underlying migraine headache. Cephalalgia :333102418771350
Zhao, Jun; Levy, Dan (2018) The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization. Pain Rep 3:e632
Zhao, Jun; Bree, Dara; Harrington, Michael G et al. (2017) Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine. Cephalalgia 37:1017-1025
Levy, Dan; Edut, Shahaf; Baraz-Goldstein, Renana et al. (2016) Responses of dural mast cells in concussive and blast models of mild traumatic brain injury in mice: Potential implications for post-traumatic headache. Cephalalgia 36:915-23
Zhao, Jun; Levy, Dan (2016) Cortical Spreading Depression Promotes Persistent Mechanical Sensitization of Intracranial Meningeal Afferents: Implications for the Intracranial Mechanosensitivity of Migraine. eNeuro 3:
Zhao, Jun; Levy, Dan (2015) Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment. J Neurophysiol 113:2778-85
Benromano, T; Defrin, R; Ahn, A H et al. (2015) Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache. Eur J Pain 19:621-8

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