REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS

DRG 神经元 T 通道的氧化还原药理学

• 批准号: 7439132
• 负责人: Slobodan M. Todorovic
• 金额: $ 28.21万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439132
• 关键词: Acids; Acute; Adult; Affect; Afferent Neurons; Amino Acids; Amplifiers; Appendix; Ascorbic Acid; Blood Vessels; Calcium; Calcium Channel; Capsaicin; Cells; Clinical; Complex; Condition; Cysteine; Data; Development; Disease; Dithionitrobenzoic Acid; Dysesthesias; Elements; Equilibrium; Fiber; Fire - disasters; Glutathione; Grant; Homocysteine; Homocystine; Hyperalgesia; In Vitro; Injury; Ion Channel; Kinetics; Lead; Ligands; Mediating; Metabolic; Mibefradil; Modeling; Molecular; Mutagenesis; Neurons; Nitric Oxide; Nociception; Nociceptive Stimulus; Nociceptors; Oxidants; Oxidation-Reduction; Pain; Pain management; Patch Tests; Pathway interactions; Perception; Peripheral; Pharmacology; Physiological; Physiology; Play; Population; Property; Public Health; Rattus; Recombinants; Reducing Agents; Reporting; Research Design; Resistance; Role; Sensory; Sensory Process; Spinal Ganglia; Staging; Steroids; Stimulus; System; T-Type Calcium Channels; Tactile; Testing; Thinking; Thioctic Acid; Time; Tissues; Whole-Cell Recordings; allodynia; base; channel blockers; chronic pain; experience; free radical oxygen; in vivo; novel; psychologic; relating to nervous system; research study; response; size; spontaneous pain; transmission process; voltage

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.

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发挥重要作用。 T型钙通道首先在感觉神经元中被描述，但由于缺乏选择性药物制剂和调节剂，理解这些通道在疼痛通路中的功能的进展受到阻碍。在分离的大鼠感觉神经元中，我们最近报道氧化还原剂调节 T 电流，但不调节其他被认为介导疼痛敏感性的电压和配体门控电流。此外，内源性氨基酸 L-半胱氨酸增加了辣椒素敏感感觉神经元的新亚群中 T 通道介导的兴奋性。因此，通过还原剂增加富含T型钙通道的感觉神经元的兴奋性可能有助于它们在体内的痛觉过敏作用。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。基于这些初步结果，我们提出外周T型钙通道可以使外周伤害感受器敏感并作为各种伤害感受刺激的通用放大器。为了检验这一假设，将进行具体实验，首先关注体外大鼠感觉神经元中 T 型钙电流氧化还原调节机制的药理学和生物物理特征。这些实验将为以后的研究奠定基础，这些研究旨在检查 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子集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处理中的作用。此外，我们的结果表明了一种尚未探索的开发潜在的疼痛控制新疗法的途径。