Chemokine ligand 2/chemokine receptor 2 signaling in the trigeminal ganglia contributes to inflammatory hyperalgesia in rats.

This study investigated the functional significance of hyperalgesia in the CCL2/CCR2 signaling system in trigeminal ganglion (TG) neurons following inflammation. Inflammation was induced by injection of complete Freund's adjuvant (CFA) into the whisker pad of rats. The escape threshold from mechanical stimulation applied to the whisker pad 2days later was significantly lower in CFA-treated rats than in naïve rats. Fluorogold (FG) labeling was used to identify the TG neurons innervating the whisker pad. FG-labeled TG neurons were immunoreactive for CCL2/CCR2. The mean number of CCL2/CCR2-immunoreactive small/medium-diameter TG neurons was significantly higher in inflamed rats than in naïve rats. Using whole-cell patch-clamp experiments in small-diameter TG neurons, the threshold current of FG-labeled TG neurons in inflamed rats was significantly decreased compared to naïve rats. The number of spike discharges during current injections by FG-labeled TG neurons in inflamed rats was significantly increased compared to naïve rats. These characteristic effects were abolished by co-application of a CCL2 receptor antagonist. The present study provides evidence that CCL2 enhances the excitability of small-diameter TG neurons following facial skin inflammation via the upregulation of CCR2. These findings suggest that ganglionic CCL2/CCR2 signaling is a therapeutic target for the treatment of trigeminal inflammatory hyperalgesia.