Migraine is a common neurological disorder characterized by severe head pain that is associated with autonomic and sensory dysfunction. Activation of cerebrovascular afferents and resultant neurogenic inflammation are thought to be essential for the development of migraine pain. Evidence suggests that inflammatory mediators such as histamine, bradykinin, and prostaglandin sensitize cerebrovascular afferents. Once sensitized, these afferents may be activated by normally innocuous stimuli, such as heart beat-induced changes in vascular pressure. Activated afferents not only release transmitters that are capable of directly stimulating afferent activity (i.e., feedback-excitation), but that drive an inflammatory response associated with the release of additional mediators that can further activate and sensitize afferent terminals. All of this afferent activity is thought to underlie at least the initiation of the pain experienced during a migraine attack. Administration of triptans is currently one of the most effective treatments for migraine pain. These drugs are serotonin receptor type 1B/1D (5-HT1B/1D) agonists. Although 5-HT1B/1D receptors are ubiquitously expressed in trigeminal and dorsal root ganglion neurons, triptans are not generally antinociceptive, having little efficacy for the treatment of pain arising from other parts of the body. Triptans have been shown to produce vasoconstriction and reduce peripheral neuropeptide expression but neither of these appears to be the primary mechanism of antinociception. Understanding the specificity associated with the anti-nociceptive action of 5-HT1B/1D receptors may provide insight into the mechanisms involved in migraine pain and help identify novel targets for drug treatment. The general hypothesis to be tested in this proposal is that the therapeutic actions of triptans reflect unique response properties of cerebrovascular afferents to inflammatory mediators. This hypothesis will be tested with experiments that examine the distribution of 5-HT1B/1D receptors among afferents innervating the intracranial vasculature and changes in excitability and synaptic transmission of cerebrovascular afferents following inflammation and triptan application. The results from these experiments should help provide unique targets for the treatment of migraine pain and increase the understanding of cerebrovascular afferent mechanisms in initiating migraine pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS059153-04
Application #
7858409
Study Section
Special Emphasis Panel (ZNS1-SRB-M (39))
Program Officer
Porter, Linda L
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$25,690
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Harriott, Andrea M; Scheff, Nicole N; Gold, Michael S (2012) The complex actions of sumatriptan on rat dural afferents. Cephalalgia 32:738-49
Vaughn, Andrea H; Gold, Michael S (2010) Ionic mechanisms underlying inflammatory mediator-induced sensitization of dural afferents. J Neurosci 30:7878-88
Harriott, Andrea M; Gold, Michael S (2009) Contribution of primary afferent channels to neuropathic pain. Curr Pain Headache Rep 13:197-207
Harriott, Andrea M; Gold, Michael S (2009) Electrophysiological properties of dural afferents in the absence and presence of inflammatory mediators. J Neurophysiol 101:3126-34
Harriott, A M; Gold, M S (2008) Serotonin type 1D receptors (5HTR) are differentially distributed in nerve fibres innervating craniofacial tissues. Cephalalgia 28:933-44