Impaired Basal Forebrain Cholinergic Neuron GDNF Signaling Contributes to Perioperative Sleep Deprivation–Induced Chronicity of Postsurgical Pain in Mice Through Regulating Cholinergic Neuronal Activity, Apoptosis, and Autophagy

ABSTRACT Aims 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. Methods 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. Results 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. Conclusions Perioperative sleep deprivation promotes chronicity of postsurgical pain possibly through decreasing basal forebrain GDNF signaling and causing cholinergic neuronal apoptosis and autophagy dysfunction. Surgery combined with perioperative sleep deprivation induces decreased GDNF in the lateral basal forebrain, which leads to enhanced apoptosis and autophagy dysfunction of cholinergic neurons and increased risk of chronic postsurgical pain. Normalizing GDNF levels by AAV‐GDNF therapy rescues the deleterious effects of perioperative sleep deprivation. Select