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Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
Targeting CXCR2 in Nociceptive Sensory Neurons Offers Novel Therapeutic Potentials for Postoperative Pain
Yushuang Pan1, Peiyi Li1, Yufeng Chen1
1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China.
Abstract:
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.
Insights
Chemokine CXCL5 (chemoattractant cytokine ligand 5) drives postoperative pain by activating CXCR2 on sensory neurons. Targeting this pathway offers pain relief without hindering wound healing.
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Postoperative pain significantly impacts patient quality of life.
- The underlying mechanisms of postoperative pain are not fully understood.
- CXCL5 is identified as a key molecule in pain signaling.
Purpose of the Study:
- To investigate the role of CXCL5 and its receptor CXCR2 in postoperative incisional pain (INC).
- To explore the therapeutic potential of targeting the CXCL5-CXCR2 axis in sensory neurons for pain management.
Main Methods:
- Utilized a mouse model of skin and deep tissue incision (INC).
- Employed gene expression analysis, single-cell RNA-sequencing, and neutralizing antibodies.
- Generated global and conditional knockout mice for CXCR2.
- Investigated neuronal excitability and ion channel function (TRPA1, TRPV1) in dorsal root ganglion (DRG) neurons.
Main Results:
- CXCL5 expression was upregulated at the incision site and in human skin wounds.
- Neutralizing CXCL5 or knocking out CXCR2 in sensory neurons reduced INC pain.
- Global CXCR2 knockout improved pain but delayed wound healing.
- CXCR2 signaling in DRG neurons enhanced TRPA1 and TRPV1 activity, contributing to hypersensitivity.
- Targeted knockdown of CXCR2 in sensory neurons alleviated pain without affecting wound healing.
Conclusions:
- Neuronal CXCR2 signaling is critical for mediating INC pain by modulating TRPA1 and TRPV1 channels.
- Targeting sensory neuronal CXCR2 is a promising strategy for managing postoperative pain.
- This approach offers pain relief without compromising wound healing or local inflammation.
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