Unexpected Role of TNFα Signaling in the Resolution of Postoperative Pain in Mice

Sophie Laumet, Aaryn M Edwards, Kufreobong E Inyang, Geoffroy Laumet Department of Physiology, Michigan State University, East Lansing, MI, USACorrespondence: Geoffroy Laumet, Department of Physiology, Michigan State University, 766 Service Road, East Lansing, MI, 48864, USA, Email [email protected]: The mechanisms that govern the transition from acute to chronic pain remain poorly defined. Emerging evidence suggests that immune cells and acute inflammatory responses are not merely pathological but actively contribute to pain resolution and the prevention of chronic pain. Using a mouse model of postoperative pain induced by plantar incision, we demonstrate that inhibition of tumor necrosis factor (TNFα) signaling prolongs pain hypersensitivity. Intraplantar administration of either monoclonal or polyclonal neutralizing anti-TNFα antibodies or Etanercept, a TNF receptor decoy, significantly delayed the resolution of pain in both female and male mice. Unexpectedly, early blockade of TNFα signaling did not reduce pain hypersensitivity but instead extended its duration. These findings underscore a paradoxical yet critical role for TNFα and immune signaling in promoting the resolution of acute pain and preventing its persistence. Together it supports the concept that acute inflammation and immune cells are essential for initiating the resolution of pain.Keywords: TNFα, postoperative pain, pain resolution, inflammation, mice