Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats.
Aspirin-triggered Lipoxin A4 (ATL), as a Lipoxin A4 (LXA4) epimer, is endogenously produced by aspirin-acetylated cycloxygenase-2 (COX-2) and plays a vital role in endogenous anti-inflammation via the LXA4 receptor (ALX). Recent investigations have indicated that spinal neuroinflammation and the activation of the Janus Kinase 2 (JAK2)/Signal Transducers and Transcription Activators 3 (STAT3) signaling pathway are involved in neuropathic pain states. However, the effect of ATL on neuroinflammation and JAK2/STAT3 signaling in chronic constriction injury (CCI)-induced neuropathic pain in rats has not been well-studied. The present study demonstrated the anti-inflammatory and analgesic effect of ATL on neuropathic pain and assessed the role of spinal JAK2/STAT3 signaling on the effect of ATL. Intrathecal administration of ATL significantly attenuated mechanical allodynia via spinal ALX and inhibited the upregulation of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) on day 7 of CCI surgery. In addition, ATL markedly suppressed the upregulation of p-STAT3 induced by the neuropathic pain. Blockade of JAK2-STAT3 signaling with intrathecal administration of the JAK2 inhibitor AG490 or the STAT3 inhibitor S3I-201 clearly reduced mechanical allodynia and the upregulation of pro-inflammatory cytokines in CCI rats. Interestingly, inhibition of JAK2/STAT3 signaling via ATL or the specific signaling inhibitor (AG49, S3I-201) further promoted the increased expression of suppressor of cytokine signaling 3 (SOCS3) mRNA in the spinal cord induced by CCI surgery. Taken together, our results suggested that the analgesic effect of ATL was mediated by inhibiting spinal JAK2/STAT3 signaling and hence the spinal neuroinflammation in CCI rats.
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China; Department of Anatomy, Integrative Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China. Electronic address: wzf993002@163.com.
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Wang
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: lqianan2008@126.com.
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Li
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: 781667612@qq.com.
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Liu
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: wenlimi@fudan.edu.cn.
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Mi
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: hushan0322141@126.com.
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Hu
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: 10210700038@fudan.edu.cn.
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Zhao
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: 10111010019@fudan.edu.cn.
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Tian
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: maoyql@fudan.edu.cn.
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Mao-Ying
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: wu007@shmu.edu.cn.
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Jiang
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: hjma@shmu.edu.cn.
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Ma
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: wangyanqing@shmu.edu.cn.
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YQ
Wang
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: gcwu@shmu.edu.cn.
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Wu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001241:Aspirin / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D044045:Lipoxins / Q000008:administration & dosage*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014110:Touch; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D044045:Lipoxins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D001241:Aspirin
JAK2/STAT3; aspirin-triggered Lipoxin A(4); inflammation; neuropathic pain; spinal cord