Mast cell-specific receptor MrgprB2 selectively mediates oxaliplatin-induced neuropathic pain

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) causes debilitating pain that limits anticancer treatment, yet effective therapies remain limited. Mast cells (MCs) regulate neuroimmune signaling implicated in CIPN, but their receptor-specific contributions remain poorly understood. In mice, oxaliplatin and paclitaxel produce robust mechanical and cold hypersensitivities that mirror CIPN pain. Mas-related G-protein-coupled receptor B2 (MrgprB2) and its human orthologue MrgprX2 are MC-restricted receptors that mediate non-IgE-mediated activation. However, whether MrgprB2 signaling differently contributes to oxaliplatin- versus paclitaxel-induced CIPN pain remains unclear. METHODS: We employed a comparative mechanistic approach using wild-type (WT) and MrgprB2 knockout (KO) mice to define receptor-specific contributions to oxaliplatin- versus paclitaxel-induced CIPN pain. Behavioral assessments of mechanical and cold hypersensitivity were integrated with histological profiling of MC recruitment and mediator profiles. Genetic findings were validated pharmacologically with osthole, a natural MrgprB2/X2 antagonist. RESULTS: Both oxaliplatin and paclitaxel induced cutaneous MC accumulation in the hindpaw of WT mice, but they triggered distinct MC mediator-release profiles in vivo: oxaliplatin preferentially elevated tryptase, while paclitaxel was associated with greater histamine enrichment. Yet, neither drug directly activate MCs in vitro, as indicated by unchanged β-hexosaminidase release and calcium signaling. Importantly, MrgprB2 KO selectively attenuated oxaliplatin-induced tryptase upregulation and mechanical and cold hypersensitivity in vivo, without affecting paclitaxel-induced histamine changes or pain behavior. Consistently, with these genetic results, osthole selectively attenuated oxaliplatin-induced pain, but not paclitaxel-induced pain in WT mice. CONCLUSIONS: These findings support a mechanistic dichotomy in CIPN pain, indicating that MrgprB2 contributes selectively to oxaliplatin-induced, but not paclitaxel-induced, CIPN in mice. More broadly, they suggest that CIPN involves mechanistically distinct neuroimmune states depending on the chemotherapeutic class and highlight MrgprB2/X2 as a drug class-selective target for platinum-induced CIPN pain treatment.