REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS

描述(申请人提供)：疼痛是一个重要的临床问题，来自体外和体内研究的越来越多的证据表明，调节T型电压门控钙通道的氧化还原试剂在感觉传递中发挥着重要作用。T型钙通道最早是在感觉神经元中被描述的，但由于缺乏选择性的药理药物和调节剂，对这些通道在疼痛通路中的功能的了解一直受到阻碍。在分离的大鼠感觉神经元中，我们最近报道了氧化还原剂调节T-电流，但不调节其他被认为介导疼痛敏感性的电压和配基门控电流。此外，内源性氨基酸L-半胱氨酸增加了一种新的辣椒素敏感感觉神经元亚群中T通道介导的兴奋性。因此，在体内，富含T型钙通道的感觉神经元的兴奋性增加可能与其痛觉过敏效应有关。这些数据首次有力地表明了T通道在外周疼痛传递中的新作用。在这些初步结果的基础上，我们认为外周T型钙通道可以敏化外周伤害性感受器，并作为各种伤害性刺激的通用放大器。为了验证这一假说，我们将进行特定的实验，首先集中在体外大鼠感觉神经元T型钙电流氧化还原调节机制的药理学和生物物理特征上。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，以及T电流在调节已识别的感觉神经元亚群的兴奋性方面的生理作用。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，我们的研究结果还为疼痛控制的潜在新疗法的开发提供了一条尚未探索的途径。

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.