Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Chemotherapy-induced neuropathic pain (CIPN) is a debilitating condition with limited treatment options.
• The complement system, particularly C3, plays a role in CIPN pathogenesis, but the precise mechanisms are unclear.
• C3a, a product of complement activation, mediates inflammation via its receptor, C3aR1.

Purpose of the Study:

• To elucidate the mechanism by which complement C3a receptor 1 (C3aR1) contributes to paclitaxel-induced neuropathic pain (PIMA).
• To investigate the role of C3aR1 in regulating dorsal root ganglion (DRG) macrophages and TRPV4 expression in PIMA.
• To evaluate C3aR1 antagonism as a potential therapeutic strategy for CIPN.

Main Methods:

• Compared PIMA severity, DRG macrophage infiltration, and TRPV4 expression in wild-type (WT) and C3aR1 knockout (KO) mice treated with paclitaxel.
• Administered a C3aR1 antagonist to WT mice and rats to assess its effects on PIMA and related molecular/cellular changes.
• Investigated the protective effect of C3aR1 antagonist in TRPV4 KO mice.

Main Results:

• Paclitaxel treatment increased C3aR1 expression on DRG macrophages and induced macrophage expansion in WT but not C3aR1 KO mice.
• C3aR1 KO mice exhibited reduced PIMA severity and lower DRG TRPV4 expression compared to WT mice.
• C3aR1 antagonist administration attenuated PIMA, downregulated DRG TRPV4, reduced macrophage expansion, suppressed neuron hyperexcitability, and alleviated nerve fiber loss in WT mice and rats.
• C3aR1 antagonist provided additional protection in TRPV4 KO mice.

Conclusions:

• Complement C3aR1 signaling upregulates TRPV4 expression on DRG neurons and promotes DRG macrophage expansion, contributing to PIMA.
• Targeting C3aR1 represents a promising therapeutic avenue for managing chemotherapy-induced neuropathic pain.