Integrated stress response and postoperative neuroinflammation in veterinary surgery: Therapeutic perspectives

Abstract

Postoperative inflammation and pain remain major challenges in veterinary surgery, significantly affecting tissue healing, recovery time, and overall patient welfare. Surgical trauma activates a complex physiological response involving neuroendocrine stimulation, inflammatory mediator release, oxidative stress, and immune dysregulation. Central to these processes is the Integrated Stress Response (ISR), a highly conserved intracellular signaling pathway that regulates cellular adaptation during physiological stress. Activation of ISR-associated pathways, particularly PERK-eIF2-ATF4 signaling, initially promotes cellular survival and restoration of proteostasis; however, prolonged activation may contribute to apoptosis, neuroinflammation, delayed healing, and chronic pain sensitization. Current perioperative management in veterinary medicine primarily relies on multimodal analgesic protocols including NSAIDs, opioids, alpha-2 adrenergic agonists, NMDA receptor antagonists, and local anaesthetics. Although these therapies effectively reduce nociceptive signaling and inflammation, they are often associated with adverse effects such as gastrointestinal toxicity, renal injury, immunosuppression, and delayed tissue repair. Consequently, recent research has increasingly focused on targeted pharmacological approaches that modulate upstream cellular stress pathways and inflammatory signaling networks. Emerging therapies such as ISR modulators, antioxidant compounds, anti-cytokine strategies, and immunomodulatory agents show promise in reducing oxidative injury, preserving cellular homeostasis, and improving perioperative outcomes. Advances in precision perioperative medicine, including biomarker guided analgesia, opioid-sparing anaesthesia, and species specific multimodal protocols, may further enhance recovery and minimize postoperative complications in veterinary patients. Understanding the molecular interactions between surgical stress, neuroinflammation, and ISR activation could provide novel therapeutic targets for improving pain management, accelerating wound healing, and optimizing welfare across diverse veterinary species.