Recurrent and intractable chronic itch is a worldwide problem, but mechanisms, especially the neural mechanisms, underlying chronic itch still remain unclear. In this study, we investigated the peripheral and spinal mechanisms responsible for prolonged itch in a mouse model of allergic contact dermatitis induced by squaric acid dibutylester. We found that repeated exposure of mice to squaric acid dibutylester evoked persistent spontaneous scratching and significantly aberrant cutaneous and systemic immune responses lasting for weeks. Squaric acid dibutylester–induced itch requires both nonhistaminergic and histaminergic pathways, which are likely relayed by GRPR and NPRA in the spinal cord, respectively. Employing genetic, pharmacologic, RNAscope assay, and cell-specific ablation methods, we dissected a neural circuit for prolonged itch formed as Grpr⁺ neurons act downstream of Npr1⁺ neurons in the spinal cord. Taken together, our data suggested that targeting GRPR and NPRA may provide effective treatments for allergic contact dermatitis–associated chronic pruritus.

复发性和顽固性慢性瘙痒是一个世界性的问题，但是尚不清楚潜在的慢性瘙痒的机制，尤其是神经机制。在这项研究中，我们调查了由方酸二丁酯引起的过敏性接触性皮炎小鼠模型中瘙痒延长的外周和脊髓机制。我们发现，小鼠反复暴露于方酸二丁酯会引起持续的自发性抓挠，并持续数周的明显异常的皮肤和全身免疫反应。方酸二丁酯引起的瘙痒需要非组织胺能途径和组织胺能途径，这可能分别由脊髓中的GRPR和NPRA传递。我们采用遗传学，药理学，RNAscope分析和细胞特异性消融方法，解剖了神经回路，以形成如下的长痒感：Grpr ⁺神经元在脊髓中Npr1 ⁺神经元的下游起作用。综上所述，我们的数据表明，针对GRPR和NPRA靶向治疗可能为过敏性接触性皮炎相关的慢性瘙痒症提供有效的治疗方法。