We propose to study a novel mechanism by which sensory neurons detect noxious stimuli. The ability to detect noxious stimuli is critical to survival, but can also be the source of unwanted pain. Injurious chemical, thermal and mechanical stimuli are transduced by a variety of G-protein coupled receptors and ion channels expressed in nociceptive sensory neurons. The signaling pathways in these neurons are undoubtedly complex, but deciphering these pathways promises the potential for improved treatment of pain-the most frequently cited health-care concern. One newly identified mode of noxious signaling occurs via the electrostatic charge of cations. Extracellular cations and polyamines can directly sensitize and gate the capsaicin receptor TRPV1, an ion channel essential for the development of inflammatory hyperalgesia. An important question arising from this observation is whether basic peptides can similarly modulate the function of TRPV1 and thereby regulate sensory nerve excitability. Immune and epithelial cells secrete an array of highly charged, cationic proteins and peptides. Importantly, levels of these cations are markedly elevated in inflamed tissue, however despite this observation;their effects on sensory nerve function have barely been explored. We hypothesize that polycations and cationic peptides can regulate the excitability of nociceptors through the modulation of TRPV1. We will test this innovative hypothesis using a combination of robust electrophysiological and biochemical methodologies:
In Aim 1 we will determine the activation and sensitization of TRPV1 by several inflammatory cationic peptides/proteins.
In Aim 2 we will explore the ability of polyamines and cationic peptides to trigger neuropeptide secretion from peripheral and central terminals of sensory nerve preparations.
In Aim 3 we plan to identify nociceptive behaviors and pathology arising from cationic regulation of TRPV1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055023-03
Application #
7644993
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-07-15
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$284,831
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Ahern, Gerard P (2011) 5-HT and the immune system. Curr Opin Pharmacol 11:29-33
Motter, Arianne L; Ahern, Gerard P (2008) TRPV1-null mice are protected from diet-induced obesity. FEBS Lett 582:2257-62
Matta, Jose A; Ahern, Gerard P (2007) Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585:469-82