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Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats.
Neuroscience. 2014 Jul 25; 273:65-78.N

Abstract

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24836854

Citation

Wang, Z F., et al. "Aspirin-triggered Lipoxin A4 Attenuates Mechanical Allodynia in Association With Inhibiting Spinal JAK2/STAT3 Signaling in Neuropathic Pain in Rats." Neuroscience, vol. 273, 2014, pp. 65-78.
Wang ZF, Li Q, Liu SB, et al. Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience. 2014;273:65-78.
Wang, Z. F., Li, Q., Liu, S. B., Mi, W. L., Hu, S., Zhao, J., Tian, Y., Mao-Ying, Q. L., Jiang, J. W., Ma, H. J., Wang, Y. Q., & Wu, G. C. (2014). Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience, 273, 65-78. https://doi.org/10.1016/j.neuroscience.2014.04.052
Wang ZF, et al. Aspirin-triggered Lipoxin A4 Attenuates Mechanical Allodynia in Association With Inhibiting Spinal JAK2/STAT3 Signaling in Neuropathic Pain in Rats. Neuroscience. 2014 Jul 25;273:65-78. PubMed PMID: 24836854.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. AU - Wang,Z F, AU - Li,Q, AU - Liu,S B, AU - Mi,W-L, AU - Hu,S, AU - Zhao,J, AU - Tian,Y, AU - Mao-Ying,Q L, AU - Jiang,J W, AU - Ma,H J, AU - Wang,Y Q, AU - Wu,G C, Y1 - 2014/05/14/ PY - 2013/12/01/received PY - 2014/04/21/revised PY - 2014/04/21/accepted PY - 2014/5/20/entrez PY - 2014/5/20/pubmed PY - 2015/2/11/medline KW - JAK2/STAT3 KW - aspirin-triggered Lipoxin A(4) KW - inflammation KW - neuropathic pain KW - spinal cord SP - 65 EP - 78 JF - Neuroscience JO - Neuroscience VL - 273 N2 - 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. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24836854/Aspirin_triggered_Lipoxin_A4_attenuates_mechanical_allodynia_in_association_with_inhibiting_spinal_JAK2/STAT3_signaling_in_neuropathic_pain_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00364-9 DB - PRIME DP - Unbound Medicine ER -