Davidson Steve, Copits Bryan A, Zhang Jingming, Page Guy, Ghetti Andrea, Gereau Robert W
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA AnaBios Corporation, San Diego, CA 92109, USA.
Pain. 2014 Sep;155(9):1861-1870. doi: 10.1016/j.pain.2014.06.017. Epub 2014 Jun 25.
Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50 μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. A high proportion of hDRG neurons were responsive to the algogens allyl isothiocyanate (AITC) and ATP, as well as the pruritogens histamine and chloroquine. We show that a subset of hDRG neurons responded to the inflammatory compounds bradykinin and prostaglandin E2 with action potential discharge and show evidence of sensitization including lower rheobase. Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.
人类与模式生物在感觉处理方面的生物学差异可能对慢性疼痛治疗的转化方法构成重大障碍。为了更好地理解人类感觉神经元的生理学，我们对来自5名无慢性疼痛的年轻成年供体的141个人类背根神经节（hDRG）神经元进行了全细胞膜片钳记录。几乎所有小直径hDRG神经元（<50μm）在动作电位的下降斜率上都有一个拐点，这是啮齿动物伤害性神经元的一个特征性标志。高比例的hDRG神经元对致痛物质异硫氰酸烯丙酯（AITC）和ATP以及致痒物质组胺和氯喹有反应。我们发现，一部分hDRG神经元对炎症化合物缓激肽和前列腺素E2产生动作电位发放反应，并表现出敏化迹象，包括更低的基强度。与电诱发动作电位相比，化学诱导动作电位从较低的去极化阈值触发，并表现出明显的超极化后动力学。这些数据表明，大多数中小直径hDRG神经元可归类为伤害感受器，它们直接对产生疼痛和瘙痒的化合物作出反应，并且可被炎症介质激活和敏化。本文还讨论了使用hDRG神经元作为靶点验证的临床前载体。
