• Rao Sun, Yue Liu, Bailing Hou, Yishan Lei, Jinhua Bo, Wei Zhang, Yu'E Sun, Ying Zhang, Zuoxia Zhang, Zhe Liu, Wenwen Huo, Yanting Mao, Zhengliang Ma, and Xiaoping Gu.
• Department of Anesthesiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China; Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
• Brain Behav. Immun. 2019 Jul 1; 79: 294-308.

AbstractPreoperative stress could delay the recovery of postoperative pain and has been reported to be a risk factor for chronic postsurgical pain. As stress could facilitate the proinflammatory activation of microglia, we hypothesized that these cells may play a vital role in the development of preoperative stress-induced pain chronification after surgery. Our experiments were conducted in a rat model that consists of a single prolonged stress (SPS) procedure and plantar incision. A previous SPS exposure induced anxiety-like behaviors, prolonged incision-induced mechanical allodynia, and potentiated the activation of spinal microglia. Based on the results from ex vivo experiments, spinal microglia isolated from SPS-exposed rats secreted more proinflammatory cytokines upon challenge with LPS. Our results also demonstrated that microglia played a more important role than astrocytes in the initiation of SPS-induced prolongation of postsurgical pain. We further explored the therapeutic potential of agonism of α7 nAChR, an emerging anti-inflammatory target, for SPS-induced prolongation of postsurgical pain. Multiple intrathecal (i.t.) injections of PHA-543613 (an α7 nAChR agonist) or PNU-120596 (a type II positive allosteric modulator) during the perioperative period shortened the duration of postsurgical pain after SPS and suppressed SPS-potentiated microglia activation, but their effects were abolished by pretreatment with methyllycaconitine (an α7 nAChR antagonist; i.t.). Based on the results from ex vivo experiments, the anti-inflammatory effects of PHA-543613 and PNU-120596 may have been achieved by the direct modulation of microglia. In conclusion, stress-induced priming of spinal microglia played a key role in the initiation of preoperative stress-induced prolongation of postsurgical pain, and PHA-543613 and PNU-120596 may be potential candidates for preventing pain chronification after surgery.Copyright © 2019 Elsevier Inc. All rights reserved.

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