Targeting CXCR2 in Nociceptive Sensory Neurons Offers Novel Therapeutic Potentials for Postoperative Pain
Yushuang Pan, Peiyi Li, Yufeng Chen, Zishan Dong, Yuanyuan Li, Boyu Liu, Yan Tai, Chuan Wang, Jianqiao Fang, Chengyu Yin, Boyi LiuABSTRACT
Postoperative pain impairs patients’ quality of life. Mechanisms underlying postoperative pain remain incompletely understood. We investigated postoperative pain in a mouse model of skin plus deep tissue incision (INC). We found Cxcl5 was among the top upregulated genes in incision site, which was produced from both incised skin and muscle. Single‐cell RNA‐sequencing reveals elevated human CXCL5 gene expression in human skin wounds. Neutralizing CXCL5 abrogated INC pain. Global knockout of CXCL5 receptor CXCR2 improved INC pain, but markedly delayed wound healing. Cxcr2 conditional knockout in nociceptive sensory neurons improved INC pain without affecting wound healing and local inflammation. CXCR2 expression and its coupling with TRPA1 were enhanced in DRG neurons innervating the incised site, resulting in neuron hyperexcitability upon CXCL5 stimulation. CXCL5 further enhances TRPV1 activity via neuronal CXCR2‐mediated signaling in DRG neurons innervating the incised site. Neuronal CXCR2‐mediated TRPV1/TRPA1 modulation synergistically contributes to heat and mechanical hypersensitivities of INC pain. Targeted Cxcr2 knockdown in incision site‐innervating DRG neurons ameliorates INC pain. Our work reveals a critical role of neuronal CXCR2 signaling in nociceptive sensory neurons that mediates INC pain via concurrently activating TRPA1 and sensitizing TRPV1. Targeting sensory neuronal CXCR2 represents a promising strategy for INC pain without affecting wound healing.