REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS

描述（由申请人提供）：疼痛是一个重要的临床问题，越来越多的体外和体内研究证据表明，调节T型电压门控钙通道的氧化还原剂在感觉传递中起重要作用。T型钙通道首先在感觉神经元中被描述，但是由于缺乏选择性的药理学试剂和调节剂，在理解这些通道在疼痛通路中的功能方面的进展受到阻碍。在离体大鼠感觉神经元，我们最近报道，氧化还原剂调节T电流，但不是其他电压和配体门控电流被认为是介导疼痛敏感性。此外，内源性氨基酸L-半胱氨酸增加T-通道介导的兴奋性在一个新的辣椒素敏感的感觉神经元亚群。因此，增加兴奋性的感觉神经元，富含T-型钙通道的还原剂可能有助于其在体内的痛觉过敏效应。这些数据首次强烈表明T通道在外周疼痛传递中的新作用。根据这些初步结果，我们认为外周T型钙通道可以敏感外周伤害感受器，并作为各种伤害性刺激的一般放大器。为了验证这一假设，将进行具体的实验，最初集中在药理学和生物物理学表征的机制，氧化还原调节T型钙电流在大鼠感觉神经元体外。这些实验将为以后的研究奠定基础，这些研究旨在研究T通道氧化还原调节的分子基础和T电流在调节已识别的感觉神经元亚群的兴奋性中的生理作用。因此，对T型钙通道的氧化还原药理学和生理学的研究可能有助于阐明这些通道在感觉加工中的作用。此外，我们的研究结果为开发潜在的疼痛控制新疗法提供了一条未探索的途径。

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.