Zavala K, Lee J, Chong J, Sharma M, Eilers H, Schumacher M A
Department of Anesthesia and Perioperative Care, Division of Pain Medicine, University of California, San Francisco 94143-0427, United States.
Department of Anesthesia and Perioperative Care, Division of Pain Medicine, University of California, San Francisco 94143-0427, United States.
Neurosci Lett. 2014 Aug 22;578:211-6. doi: 10.1016/j.neulet.2014.01.021. Epub 2014 Jan 25.
Activation of peripheral nociceptors by products of inflammation has been shown to be dependent on specific sensory transducing elements such as the capsaicin receptor, TRPV1. The development of high-affinity antagonists to TRPV1 as well as to other receptors capable of detecting noxious stimuli has now become a major focus in analgesic development. Another critical feature of nociception is the relative abundance of a particular pain transducing receptor under normal or pathophysiologic conditions. Increases in expression and/or changes in distribution of nociceptive receptors such as TRPV1 have been correlated with progression of tissue injury and persistence of pain behaviors. Although some details are emerging as to what regulates nociceptor-specific gene expression, compounds that could potentially be used to block or reverse over-expression of nociceptive gene expression are essentially absent. In our efforts to better understand the transcriptional regulation of TRPV1 in sensory neurons, we identified an anticancer agent, mithramycin-A, that decreased TRPV1 expression in primary rat dorsal root ganglion (DRG) neurons. Mithramycin-A dose-dependently (10-50 nM) decreased endogenous TRPV1 mRNA content and appeared to decrease TRPV1-like protein expression in DRG neurons. We also observed that mithramycin-A directed a decrease in the number of capsaicin-responsive DRG neurons without a significant change in the capsaicin-response magnitudes. Interestingly, mithramycin-A also reduced the mRNA encoding Sp1 and Sp4 in DRG neurons, transcription factors previously found to positively regulate TRPV1 expression in sensory neurons. Taken together, we propose that mithramycin-A directs an inhibitory effect on a subpopulation of capsaicin-responsive DRG neurons that utilize Sp1-like factors for TRPV1 expression. Given the therapeutic correlate of mithramycin-A effectiveness in the treatment of certain cancers, small molecule transcriptional inhibitors such as mithramycin-A may serve as useful tools of discovery in pain transduction and possibly future analgesic development.
炎症产物激活外周伤害感受器已被证明依赖于特定的感觉转导元件，如辣椒素受体TRPV1。开发针对TRPV1以及其他能够检测有害刺激的受体的高亲和力拮抗剂，现已成为镇痛药物研发的主要焦点。伤害感受的另一个关键特征是在正常或病理生理条件下特定疼痛转导受体的相对丰度。伤害性感受器（如TRPV1）的表达增加和/或分布变化与组织损伤的进展和疼痛行为的持续存在相关。尽管关于调节伤害感受器特异性基因表达的机制已逐渐明晰，但能够潜在地用于阻断或逆转伤害性基因表达过表达的化合物却基本不存在。在我们为更好地理解感觉神经元中TRPV1的转录调控所做的努力中，我们发现了一种抗癌药物——光神霉素A，它能降低原代大鼠背根神经节（DRG）神经元中TRPV1的表达。光神霉素A剂量依赖性地（10 - 50 nM）降低内源性TRPV1 mRNA含量，并似乎降低了DRG神经元中TRPV1样蛋白的表达。我们还观察到，光神霉素A使辣椒素反应性DRG神经元的数量减少，而辣椒素反应幅度没有显著变化。有趣的是，光神霉素A还降低了DRG神经元中编码Sp1和Sp4的mRNA水平，此前发现这些转录因子可正向调节感觉神经元中TRPV1的表达。综上所述，我们认为光神霉素A对利用Sp1样因子进行TRPV1表达的辣椒素反应性DRG神经元亚群具有抑制作用。鉴于光神霉素A在治疗某些癌症方面的疗效具有治疗相关性，像光神霉素A这样的小分子转录抑制剂可能成为疼痛转导研究以及未来镇痛药物研发中有用的发现工具。
