Pain is an important clinical problem and there is growing evidence from both in vitro and in vivo studies that redox agents that modulate T-type voltage-gated calcium channels play an important role in sensory transmission. T-type calcium channels were first described in sensory neurons but progress in understanding the function of these channels in pain pathways has been hindered by the lack of selective pharmacological agents and modulators. In isolated rat sensory neurons, we recently reported that redox agents modulate T-currents but not other voltage- and ligand-gated currents thought to mediate pain sensitivity. Furthermore, the endogenous amino acid L-cysteine increased T-channel-mediated excitability in a novel subpopulation of capsaicin-sensitive sensory neurons. Thus, increase in excitability of sensory neurons that are enriched in T-type calcium channels by reducing agents may contribute to their hyperalgesic effect in vivo. These data for the first time strongly suggest a novel role for T-channels in peripheral pain transmission. On the basis of these preliminary results, we propose that peripheral T-type calcium channels can sensitize peripheral nociceptors and serve as general amplifiers of various nociceptive stimuli. To test this hypothesis, specific experiments will be performed focusing initially on the pharmacological and biophysical characterization of mechanisms underlying redox modulation of T-type calcium currents in rat sensory neurons in vitro. These experiments will set the stage for later studies designed to examine the molecular basis of redox modulation of T channels and physiological roles of T-currents in regulating the excitability of identified subsets of sensory neurons. Thus, studies of redox pharmacology and physiology of T-type calcium channels may help to elucidate roles of these channels in sensory processing. In addition, our results suggest an unexplored avenue for the development of potential novel therapies for pain control. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM075229-01A1
Application #
7090964
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Cole, Alison E
Project Start
2006-06-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$290,772
Indirect Cost
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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