Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice

Inhibition of tumor necrosis factor-alpha (TNF alpha) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNF alpha signaling and the role of superoxide anion in TNF alpha-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5 h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNF alpha actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1-/- mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFa-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNF alpha/TNFR1 signaling is important in superoxide anion-triggered pain and that TNF alpha/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.