Formalin Itch Test: Low-Dose Formalin Induces Histamine-Independent, TRPA1-Mediated Itch in Mice

Frontiers in Medicine

Jiang Ji¹  Xu Liu²  Tong Liu³  Wen-Qi Shan⁴  Qing-Yue Fu⁴  Jiang-Tao Zhang⁴  Yue Hu⁴  Zhi-Hong Wang⁴  Dan-Ni Fu⁴ 

[1] Department of Dermatology, The Second Affiliated Hospital of Soochow University, Suzhou, China;Department of Dermatology, The Second Affiliated Hospital of Soochow University, Suzhou, China;Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China;Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, China;College of Life Sciences, Yanan University, Yanan, China;Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China;

关键词: itch;    pain;    formalin;    TRPA1;    dorsal root ganglion;   

DOI  :  10.3389/fmed.2021.627725

来源: Frontiers

【 摘 要 】

Chronic itch is a common distressing symptom of many diseases, which reduced patient's quality of life. The mechanistic study on itch and screening for new anti-itch drugs require the development of new pre-clinical itch animal models. Herein, we established an acute itch model by intradermal (i.d.) injection of low-dose formalin into the neck or cheek in mice. In mice, i.d. injection of formalin (0.1–5%) in the nape of the neck evoked robust scratching behavior in a dose-dependent manner and the dose–response curves showed an inverted “U” shape. I.d. injection of formalin (0.3–0.6%) into the cheek evoked scratching in mice but wiping in rats, while formalin (1.25–5%) induced mixed wiping and scratching behavior in both mice and rats. Further, we found that 0.3% formalin-induced scratching was histamine-independent and significantly attenuated by transient receptor potential ion channel A1 (TRPA1) inhibitor (HC030031) or in TRPA1 knockout (KO) mice, but not affected by transient receptor potential ion channel V1 (TRPV1) inhibitor (capsazepine) or in TRPV1 KO mice. Additionally, 0.3% formalin-induced up-regulation of phosphorylation of extracellular regulated protein kinases (p-ERK) in the dorsal root ganglion (DRG) and scratching were suppressed by intrathecal injection of MEK inhibitor U0126 in mice. Incubation of 0.03% formalin induced the accumulation of intracellular reactive oxygen species (ROS) in the cultured DRG-derived cell line ND7-23, and formalin-induced itch was suppressed by antioxidants in mice. Finally, perfusion of 0.03% formalin induced elevation of intracellular calcium in a subset of primary cultured DRG neurons of mice. Thus, these results indicate that low-dose formalin induced non-histaminergic itch by activation of TRPA1 in mice, which may be employed as a useful acute itch model for screening potential anti-itch drugs.

【 授权许可】

CC BY