Contribution of GRP-GRPR system in the spinal dorsal horn to pathological itch

Abstract

Gastrin-releasing peptide (GRP) receptor (GRPR)⁺ neurons in the spinal dorsal horn (SDH) are itch-responsive, but their regulatory mechanisms are not yet clarified. Recently, we found that not only GRP but also glutamate directly activate GRPR⁺ neurons through AMPA receptors (AMPAR), and those transmitters play fundamental roles in the spinal transmission of physiological itch. Here, we determined whether GRP-GRPR system underlies pathological itch in mice. To induce contact dermatitis, diphenylcyclopropenone (DCP) was applied to C57BL mice after having shaved on the back. The mRNA expression levels of GRP and GRPR in the cervical SDH were upregulated after DCP application. DCP-induced scratching behaviors were prevented by ablation of GRPR⁺ AMPAR⁺ neurons following bombesin-saporin treatment. Moreover, chemogenetic silencing of GRP⁺/glutamate⁺ neurons using Cre-dependent Gi- designer receptors exclusively activated by designer drugs (DREADD) also attenuated DCP-induced scratching behaviors. These results suggest that GRP-GRPR system and glutamate-AMPAR system in the SDH might cooperatively regulate not only physiological but also pathological itch.