Mas-related G protein-coupled receptors contribute to compound 48/80-induced mast cell-independent activation of dorsal root ganglion neurons and itch in mice
Ji Shi, Dong-Ye Wu, Shi-Yu Sun, Tong Liu, Bin Wu, Guo-Kun ZhouObjective
Compound 48/80 (C48/80) is widely used as a mast cell degranulator, and its pruritogenic action has generally been attributed to mast cell-derived mediators. Whether C48/80 also drives itch through a mast cell-independent neuronal mechanism remains unresolved. This study aimed to determine whether C48/80 evokes itch through direct, mast cell-independent activation of dorsal root ganglion (DRG) sensory neurons and to identify the receptors involved.
Methods
C48/80-evoked scratching was assessed in mice after resiniferatoxin (RTX)-mediated ablation of capsaicin-sensitive afferents, mast cell stabilization, antihistamine treatment, and in mast cell-deficient, transient receptor potential ankyrin 1 (Trpa1 ‐/‐ ), and transient receptor potential vanilloid 1 (Trpv1 ‐/‐ ) mice. Fura-2 ratiometric calcium imaging was performed in cultured primary DRG neurons to examine direct neuronal responses and the effects of TRPA1/TRPV1 deletion or Mas-related G protein-coupled receptor (MRGPR) blockade with Boc-Gln-D-Trp(Formyl)-Phe-OBzl (QWF).
Results
C48/80 evoked robust scratching in mice, and RTX-mediated ablation of capsaicin-sensitive afferents markedly reduced the number of scratch bouts. In contrast, cromolyn sodium or the antihistamine chlorpheniramine did not eliminate the response. C48/80 continued to elicit scratching in mast cell-deficient mice and produced comparable behavioral responses in Trpa1 ‐/‐ and Trpv1 ‐/‐ mice. In cultured primary DRG neurons, C48/80 evoked calcium responses that were not prevented by deletion of TRPA1 or TRPV1. By contrast, QWF, an MRGPR antagonist, strongly inhibited C48/80-induced calcium signaling and reduced scratch bouts after intraperitoneal administration.
Conclusion
C48/80 can directly activate DRG neurons and induce itch through a mast cell-independent neuronal pathway. MRGPR-dependent signaling, rather than TRPA1 or TRPV1, is a key contributor to this direct neuronal component of C48/80-evoked itch.