Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
Sci Transl Med. 2022 Jul 13;14(653):eabn4819. doi: 10.1126/scitranslmed.abn4819.
Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3 pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.
瘙痒感觉会引发搔抓反射，以保护我们免受皮肤中的有害刺激。虽然搔抓通过机械感受器的激活可以暂时缓解急性瘙痒，但它会随着时间的推移进一步加重瘙痒，从而使慢性瘙痒的瘙痒-搔抓循环恶化。尽管临床上已经得到很好的认识，但瘙痒-搔抓循环的外周机制仍知之甚少。在这里，我们表明皮肤的机械刺激导致 Merkel 细胞上的 Piezo2 通道激活，病理性地促进了实验性干燥皮肤中的自发性瘙痒。三维重建和免疫电子显微镜显示，在干燥皮肤的情况下，MRGPRA3 痒觉感受器神经末梢的结构发生改变，指向 Merkel 细胞。我们的结果揭示了病理条件下的功能连接错误机制，导致触觉受体触发皮肤中痒觉感受器的放电，从而驱动瘙痒-搔抓循环。
