Imperatorin activates TRPV1/GRPR pathway to induce scratching behaviors in mice.

Chronic itch is a prevalent and distressing symptom associated with several diseases, and significantly affects patients' quality of life. Investigating the mechanisms underlying itch and identifying novel anti-pruritic drugs require the development of innovative preclinical animal models. In this study, an acute animal model of itch was established using an intradermal (i.d.) injection of imperatorin (IMP) into the nape of the neck or cheek of male and female mice. The i d. IMP injection in the nape elicited a robust, dose-dependent scratching behavior that was independent of histamine. IMP injection into the cheek induced both scratching and wiping behaviors. Furthermore, IMP injection upregulated the phosphorylation of extracellular signal regulated kinases (p-ERK) and calcium influx in the dorsal root ganglion (DRG), which were suppressed by the deficiency of transient receptor potential ion channel V1 (TRPV1). Scratching behaviors could also be inhibited by TRPV1 deficiency. IMP-induced scratching could be mitigated by an intrathecal injection of the GRPR antagonist RC3095, and the IMP-evoked increase in c-Fos expression in GRPR+ neurons in the spinal cord was attenuated by TRPV1 deficiency. These findings suggest that IMP could trigger itch-related responses, at least partially, via the activation of TRPV1+ neurons in the DRG and subsequently the GRPR + neurons in the spinal cord. IMP may therefore serve as an efficient nonhistaminergic model of acute itch to screen of potential anti-pruritus agents.