Cl(-) channel is required for CXCL10-induced neuronal activation and itch response in a murine model of allergic contact dermatitis.

Persistent itch often accompanies allergic contact dermatitis (ACD), but the underlying mechanisms remain largely unexplored. We previously demonstrated that CXCL10/CXCR3 signaling activated a subpopulation of cutaneous primary sensory neurons and mediated itch response after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. The purpose of this study was to determine the ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch. In whole cell recordings, CXCL10 triggered a current in dorsal root ganglion (DRG) neurons innervating the area of CHS. This current was modulated by intracellular Cl(-) and blocked by the general Cl(-) channel inhibitors. Moreover, increasing Ca(2+) buffering capacity reduced this current. In addition, blockade of Cl(-) channels significantly suppressed CXCL10-induced Ca(2+) response. In behavioral tests, injection of CXCL10 into CHS site exacerbated itch-related scratching behaviors. Moreover, the potentiating behavioral effects of CXCL10 were attenuated by either of two Cl(-) channel blockers. Thus we suggest that the Cl(-) channel acts as a downstream target mediating the excitatory and pruritic behavioral effects of CXCL10. Cl(-) channels may provide a promising therapeutic target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.NEW & NOTEWORTHY The ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch are largely unexplored. This study revealed that CXCL10 evoked an ionic current mainly carried by Cl(-) channels. We suggest that Cl(-) channels are likely key molecular candidates responsible for the CXCL10-evoked neuronal activation and itch-like behaviors in a murine model of allergic contact dermatitis induced by the antigen squaric acid dibutylester. Cl(-) channels may emerge as a promising drug target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.