REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS

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DESCRIPTION (provided by applicant): 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.