期刊
ANESTHESIOLOGY
卷 123, 期 5, 页码 1154-1169出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ALN.0000000000000850
关键词
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资金
- National Natural Science Funds of China, Beijing, China [31000495, 81171045, 81371247, 81473749, 31421091]
- National Key Basic Research Program of China, Beijing, China [2013CB531906]
- National Natural Science Foundation of Shanghai [15ZR1402800]
- Ming-Dao Program of Fudan University, Shanghai, China [EZF101404/004/001]
Background: Emerging evidence indicates that nerve damage-initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain. Methods: The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms. Results: Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2(-/-)) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 27.3% and 266.4 +/- 83.5% (mean +/- SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2(-/-). The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2(-/-) markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium-calmodulin-dependent kinase II (CaMKII)-cyclic adenosine monophosphate response element-binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2-STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice. Conclusion: Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2-STAT3 cascade and the neuronal CaMKII-CREB cascade.
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