Wang Dong, Wei Shi-Nan, Zhang Lu, Lang Zhi-Chen, Wang Si-Nian, Cheng Bo, Lu Yan, Wang Xiu, Wang Wei, Li Feng-Sheng, Zhang Hao
The Postgraduate Training Base of Jinzhou Medical University and Department of Anesthesiology, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
Department of Anesthesiology, Tangdu Hospital, Air Force Military Medical University, Xian, Shanxi, China.
CNS Neurosci Ther. 2024 Dec;30(12):e70147. doi: 10.1111/cns.70147.
This study investigated the roles of lateral basal forebrain glial cell line-derived neurotrophic factor (GDNF) signaling and cholinergic neuron activity, apoptosis, and autophagy dysfunction in sleep deprivation-induced increased risk of chronic postsurgical pain (CPSP) in mice.
Sleep deprivation (6 h per day from -1 to 3 days postoperatively) was administered to mice receiving skin/muscle incision and retraction (SMIR) to determine whether perioperative sleep deprivation induces mechanical and thermal pain hypersensitivity, increases the risk of chronic pain, and causes changes of basal forebrain neurons activity (c-Fos immunostaining), apoptosis (cleaved Caspase-3 expression), autophagy (LC3 and p62 expression) and GDNF expression. Adeno-associated virus (AAV)-GDNF was microinjected into the basal forebrain to see whether increased GDNF expression could reverse sleep deprivation-induced changes in pain duration and cholinergic neuron apoptosis and autophagy. Cholinergic neurons were further depleted by mu p75-SAP to examine whether the pain-prolonging effects of sleep deprivation still exist.
Perioperative sleep deprivation enhanced pain sensation and prolonged pain duration in SMIR mice, which was accompanied by decreased cholinergic neuron activity and GDNF expression, increased apoptosis, and autophagy dysfunction in the substantia innominata (SI), magnocellular preoptic nucleus (MCPO), and horizontal diagonal band Broca (HDB) (hereafter lateral basal forebrain). Normalizing cholinergic neuron GDNF expression by AAV-GDNF in the lateral basal forebrain inhibited apoptosis and autophagy dysfunction and mitigated sleep deprivation-induced pain maintenance. Mice with selective lesion of lateral basal forebrain cholinergic neurons were resistant to the pain-enhancing and prolonging effects of sleep deprivation and the pain-alleviating effects of AAV-GDNF therapy.
Perioperative sleep deprivation promotes chronicity of postsurgical pain possibly through decreasing basal forebrain GDNF signaling and causing cholinergic neuronal apoptosis and autophagy dysfunction.
本研究探讨外侧基底前脑胶质细胞源性神经营养因子（GDNF）信号传导、胆碱能神经元活性、凋亡及自噬功能障碍在睡眠剥夺诱导小鼠慢性术后疼痛（CPSP）风险增加中的作用。
对接受皮肤/肌肉切开和牵拉（SMIR）的小鼠进行睡眠剥夺（术后-1至3天每天6小时），以确定围手术期睡眠剥夺是否会诱发机械性和热痛超敏反应、增加慢性疼痛风险，并导致基底前脑神经元活性（c-Fos免疫染色）、凋亡（裂解的Caspase-3表达）、自噬（LC3和p62表达）以及GDNF表达的变化。将腺相关病毒（AAV）-GDNF微量注射到基底前脑，观察GDNF表达增加是否能逆转睡眠剥夺诱导的疼痛持续时间变化以及胆碱能神经元凋亡和自噬。通过μ p75-SAP进一步消耗胆碱能神经元，以检查睡眠剥夺的疼痛延长效应是否仍然存在。
围手术期睡眠剥夺增强了SMIR小鼠的痛觉并延长了疼痛持续时间，同时伴有胆碱能神经元活性降低和GDNF表达减少，无名质（SI）、视前大细胞核（MCPO）和布罗卡水平对角带（HDB）（以下简称外侧基底前脑）的凋亡增加和自噬功能障碍。通过AAV-GDNF使外侧基底前脑胆碱能神经元GDNF表达正常化可抑制凋亡和自噬功能障碍，并减轻睡眠剥夺诱导的疼痛维持。外侧基底前脑胆碱能神经元选择性损伤的小鼠对睡眠剥夺的疼痛增强和延长效应以及AAV-GDNF治疗的疼痛减轻效应具有抗性。
围手术期睡眠剥夺可能通过降低基底前脑GDNF信号传导并导致胆碱能神经元凋亡和自噬功能障碍来促进术后疼痛的慢性化。
