title: SDF1-CXCR4 Signaling Contributes to the Transition from Acute to Chronic Pain State.
abstract: Emerging evidence has demonstrated the involvement of stromal cell-derived factor 1 (SDF1, also known as CXCL12)-CXCR4 signaling in a variety of pain state. However, the underlying mechanisms of SDF1-CXCR4 signaling leading to the maintenance of chronic pain states are poorly understood. In the present study, we sought to explore the role of SDF1-CXCR4 signaling in the forming of neuroplasticity by applying a model of the transition from acute to chronic pain state, named as hyperalgesic priming. Utilizing intraplantar bee venom (BV) injection, we successfully established hyperalgesic priming state and found that peripheral treating with AMD3100, a CXCR4 antagonist, or knocking down CXCR4 by intraganglionar CXCR4 small interfering RNA (siRNA) injection could prevent BV-induced primary mechanical hyperalgesia and hyperalgesic priming. Moreover, we showed that single intraplantar active SDF1 protein injection is sufficient to induce acute mechanical hyperalgesia and hyperalgesic priming through CXC4. Intraplantar coinjection of ERK inhibitor, U0126, and PI3K inhibitor, LY294002, as well as two protein translation inhibitors, temsirolimus and cordycepin, prevented the development of SDF1-induced acute mechanical hyperalgesia and hyperalgesic priming. Finally, on the models of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and spared nerve injury (SNI)-induced chronic neuropathic pain, we observed that knock-down of CXCR4 could both prevent the development and reverse the maintenance of chronic pain state. In conclusion, our present data suggested that through regulating ERK and PI3K-AKT pathways-mediated protein translation SDF1-CXCR4 signaling mediates the transition from acute pain to chronic pain state and finally contributes to the development and maintenance of chronic pain.
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Luo
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, China. junchen@fmmu.edu.cn.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China. junchen@fmmu.edu.cn.|Beijing Institute for Brain Disorders, Beijing, 100069, People's Republic of China. junchen@fmmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000008:administration & dosage; D054377:Chemokine CXCL12 / Q000378:metabolism*; D059350:Chronic Pain / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006930:Hyperalgesia / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction
chemical_list: D001514:Bee Venoms; D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4
keywords: Chronic pain; Hyperalgesic priming; Mechanical hyperalgesia; PGE2; Plasticity; SDF1-CXCR4 signaling