Fig. 9

Schematic representation of the regulation of the CCL2-CCR2 axis in dorsal root ganglion (DRG) following peripheral inflammation. CFA-induced inflammation provokes an increase in CCL2, CCR2, and SP mRNA expression in the ipsilateral DRG. The higher expression of CCR2 facilitates intracellular calcium mobilization induced by CCL2 and increases the release of SP and CCL2 toward the spinal cord, as well as the anterograde transport of SP toward the periphery. As shown, CCL2 can be packaged into SP-containing vesicles as well as SP-free vesicles. These two CCL2-containing populations of secretory vesicles can therefore be independently transported peripherally to the injury site and centrally to the dorsal spinal horn. By preventing CCR2 activation through repeated administration of the CCR2 antagonist, INCB3344, we found a marked reduction of the enhanced expression of CCL2 and SP mRNA, a decrease in CCR2-mediated intracellular calcium mobilization and a subsequent reduction of SP peripheral release, which significantly reduce neurogenic inflammation and hind paw edema. Altogether, preventing CCR2 activation at the DRG level contributes to reduce painful hypersensitivity and neurogenic inflammation