Keratinocyte-TRPV 1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch

• 成果类型: Article
• 署名作者: Crowther, Andrew J.; Kashem, Sakeen W.; Jewell, Madison E.; Le Chang, Henry; Midavaine, Elora; Casillas, Mariela Rosa; Danchine, Veronika; Rodriguez, Sian; Kania, Artur; Chen, Ritchie; Braz, Joao M.; Basbaum, Allan I.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; Institut de Recherche Clinique de Montreal (IRCM); Universite de Montreal; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13337
• DOI: 10.1073/pnas.2411724122
• 发表日期: 2025-06-17
• 关键词: pain; cells; touch

摘要

Our understanding of neural circuits that respond to skin dysfunction, triggering itch, and pathophysiological scratching remains incomplete. Here, we describe a profound chronic itch phenotype in transgenic mice expressing the tetracycline transactivator (tTA) gene within the Phox2a lineage. Phox2a; tTA mice exhibit intense, localized scratching and regional skin lesions, controllable by the tTA inhibitor, doxycycline. As gabapentin and the kappa opioid receptor agonist, nalfurafine, but not morphine, significantly reduce scratching, this phenotype has a pharmacological profile of neuropathic pruritus. Importantly, the Phox2a; tTA expression occurs in a spatially restricted population of skin keratinocytes that overlaps precisely with the skin area that is scratched. Localized Gi- DREADD- mediated inactivation of these Phox2a- keratinocytes completely reverses the skin lesions, while inducible tTA activation of keratinocytes initiates the scratching and skin lesions, but this occurs slowly, over a course of two months. In contrast denervation induced loss of all cutaneous input rapidly blocks scratching. These findings identify the cellular, molecular, and topographic basis of a robust and chronic sensory neuron-dependent and gabapentin- responsive neuropathic itch that is initiated by genetic factors within keratinocytes.