Qu Lintao, Fu Kai, Shimada Steven G, LaMotte Robert H
Departments of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, Maryland; and
Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.
J Neurophysiol. 2017 Jul 1;118(1):619-624. doi: 10.1152/jn.00187.2017. Epub 2017 Apr 26.
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 buffering capacity reduced this current. In addition, blockade of Cl channels significantly suppressed CXCL10-induced Ca 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. 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.
持续性瘙痒常伴随过敏性接触性皮炎（ACD），但其潜在机制在很大程度上仍未被探索。我们之前证明，在由二丁基 squarate 诱导的ACD小鼠模型接触性超敏反应（CHS）后，CXCL10/CXCR3信号激活了皮肤初级感觉神经元的一个亚群并介导了瘙痒反应。本研究的目的是确定CXCL10诱导神经元激活和过敏性瘙痒的离子机制。在全细胞记录中，CXCL10在支配CHS区域的背根神经节（DRG）神经元中引发了电流。该电流受细胞内Cl调节，并被一般的Cl通道抑制剂阻断。此外，增加Ca缓冲能力可降低该电流。另外，Cl通道的阻断显著抑制了CXCL10诱导的Ca反应。在行为测试中，将CXCL10注射到CHS部位会加剧与瘙痒相关的抓挠行为。此外，两种Cl通道阻滞剂中的任何一种都会减弱CXCL10的增强行为效应。因此，我们认为Cl通道作为下游靶点介导了CXCL10的兴奋性和瘙痒行为效应。Cl通道可能为治疗CXCL10/CXCR3信号可能参与的过敏性瘙痒提供一个有前景的治疗靶点。CXCL10诱导神经元激活和过敏性瘙痒的离子机制在很大程度上尚未被探索。本研究表明，CXCL10诱发了主要由Cl通道携带的离子电流。我们认为，在由抗原二丁基 squarate 诱导的过敏性接触性皮炎小鼠模型中，Cl通道可能是负责CXCL10诱发神经元激活和瘙痒样行为的关键分子候选者。Cl通道可能成为治疗CXCL10/CXCR3信号可能参与的过敏性瘙痒的一个有前景的药物靶点。
