Classical activation of mast cells by IgE results in the release of the monoamines such as histamine and serotonin. Mrgprb2 (murine)/MRGPRX2 (human) can be activated by various cationic substances, such as pro-adrenomedullin peptide 9–20 (PAMP 9–20), compound 48/80, drugs, neuropeptides (NPs), and host defense peptides (HDPs). Mrgbprb2-mediated activation of mast cells elicits distinct mechanisms of itch from classical IgE stimulation, in which tryptase is a major mediator while others such as histamine and serotonin are also included. Figure created with Biorender.