Review Article

Pruritus: Progress toward Pathogenesis and Treatment

Figure 2

Schematic illustration of pruritic signaling pathways. According to different responses to histamine, two signal pathways of itching are covered, namely, histamine-dependent (histaminergic) signaling pathway and histamine-independent (nonhistaminergic) signaling pathway. In the histaminergic pathway, histamine promotes PLCβ3 and PLC activation by binding to their specific receptors, particularly H1 receptor and H4 receptor. These further induce the activation of downstream target TRPV1. Then, itch signals are transferred to the central nervous system via CMi, which finally lead to itchy sensation. On the other side, many pruritogens exist in the nonhistaminergic pathway, such as cowhage, CQ, BAM8-22, SLIGRL, and β-Alanine. Cowhage initially stimulates PAR2, which in turn sensitize PLC. Then the downstream targets including TRPV1 and TRPA1 are activated. Ultimately, itch signals are transferred to the central nervous system via CMHs and itch sensation is produced. At the same time, Mrgprs are linked and activated by CQ, SLIGRL, BAM8-22, and β-Alanine, further coupled to Gβγ or PLC or other; then they promote TRPA1/ TRPV1 activation and Mrgpr-positive neurons detect itch signals; via afferent fibers (CMHs), these signals are sent to the spinal cord and are regulated by GRP-GRPR and BNP-NPRA systems; finally itching sensation is present. PLCβ3, phospholipase Cβ3; TRPV1, transient receptor potential cation channel V1; TRPA1, transient receptor potential cation channel A1; CMi, mechanically insensitive C-fibers; PAR2, protease-activated receptor; CMHs, mechanically sensitive C-type fibers; BAM8-22, bovine adrenal medulla 8-22 peptide; Mrgprs, Mas-related G protein-coupled receptors; GRP, gastrin-releasing peptide; GRPR, gastrin-releasing peptide receptor; BNP, B-type natriuretic peptide; NPRA, natriuretic peptide receptor A.