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.
Department of Anesthesiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China.
Brain Behav Immun. 2019 Jul;79:294-308. doi: 10.1016/j.bbi.2019.02.017. Epub 2019 Feb 21.
Preoperative 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.
术前应激可延迟术后疼痛的恢复，并已被报道为慢性术后疼痛的危险因素。由于应激可以促进小胶质细胞的促炎激活，我们假设这些细胞可能在手术后术前应激诱导的疼痛慢性化发展中发挥重要作用。我们的实验在一个由单次延长应激（SPS）程序和足底切口组成的大鼠模型中进行。先前的 SPS 暴露引起焦虑样行为、延长切口引起的机械性痛觉过敏，并增强了脊髓小胶质细胞的激活。基于离体实验的结果，来自 SPS 暴露大鼠的脊髓小胶质细胞在受到 LPS 刺激时分泌更多的促炎细胞因子。我们的结果还表明，小胶质细胞在 SPS 诱导的术后疼痛延长的起始中比星形胶质细胞发挥更重要的作用。我们进一步探讨了激动 α7 nAChR（一种新兴的抗炎靶点）对 SPS 诱导的术后疼痛延长的治疗潜力。在围手术期多次鞘内（i.t.）注射 PHA-543613（α7 nAChR 激动剂）或 PNU-120596（II 型正变构调节剂）可缩短 SPS 后的术后疼痛持续时间，并抑制 SPS 增强的小胶质细胞激活，但这些作用在预先用甲基-1-乙酰基-6,7-二氢-5H-吡啶并[4,3-b]吲哚（α7 nAChR 拮抗剂；i.t.）预处理后被消除。基于离体实验的结果，PHA-543613 和 PNU-120596 的抗炎作用可能是通过直接调节小胶质细胞实现的。总之，脊髓小胶质细胞的应激诱导启动在术前应激诱导的术后疼痛延长的起始中发挥关键作用，PHA-543613 和 PNU-120596 可能是预防手术后疼痛慢性化的潜在候选药物。
