Species-specific cutaneous protein signatures upon incision injury and correlation with distinct pain-related phenotypes in humans

Pain after surgery is common, and its management remains a clinical challenge. Severe acute and prolonged post-surgical pain impairs immediate recovery and leads to long-term consequences like chronic pain, opioid dependency, and reduced quality of life. Althought rodent pain incision models exist, translation to patients is still hampered. To bridge this gap, we combined sensory phenotyping with quantitative proteomics and protein networks in humans and mice after skin incision representing an established model for surgical pain. Initially, we revealed, for the first time, similarities and differences of protein-protein interaction (PPI) networks across both species. Next, we comprehensively phenotyped humans for pain-related symptoms and observed phenotypes with incision-induced proteome changes. Remarkably, post-incision PPI-networks differed between volunteers with small incision-related hyperalgesic areas ("Low responder") versus those with large areas ("High responder"). The latter exhibited a pronounced proteolytic environment associated with persistent inflammation, while an anti-inflammatory protein signature was observed in Low responders. Taken together, we provide unprecedented insights into peripheral processes relevant for developing hyperalgesia and pain after incision. This knowledge will immensely facilitate bidirectional translational pain studies and guide future research on the pathophysiology of pain after surgery and the discovery of novel targets for its treatment and prevention.