Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity

Abstract Background Pain is reported as the leading cause of disability in common forms inflammatory arthritis conditions. Acting a key player nociceptive processing, neuroinflammation, and neuron-glia communication, chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how system dorsal root ganglion (DRG) contributes to peripheral pain sensitization. Methods Repeated intrathecal ( i.t .) administration CCR2 antagonist, INCB3344 was tested its ability reverse nociceptive-related behaviors tonic formalin complete Freund’s adjuvant (CFA) models. We further determined by qPCR expression CCL2/CCR2, SP CGRP DRG neurons from CFA-treated rats. Using explants, acutely dissociated primary sensory calcium mobilization assay, also assessed release CCL2 sensitization nociceptors. Finally, examined immunohistochemistry following nerve ligation axonal transport CCL2, SP, sciatic Results first found that CFA-induced paw edema provoked an increase ipsilateral DRGs, which decreased after treatment. This upregulation pronociceptive neuromodulators accompanied enhanced neuron excitability on days 3 10 post-CFA, revealed CCR2-dependent intracellular stimulation. In demonstrated increased inflammation. excitation nociceptors inflammation stimulated anterograde at their terminals. Importantly, blockade reduced limiting subsequently towards periphery. pharmacological inhibition reversed action rats receiving injection significantly neurogenic well stimuli-evoked movement-evoked Conclusions Our results provide significant mechanistic insights into role within development inflammation, nociceptor sensitization, hypersensitivity. unveil therapeutic potential targeting treatment disorders.