Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice
Related Experiment Video
Updated: Apr 5, 2026

Author Spotlight: Enhanced Method for Evaluating Analgesic Effects — Dual Hind Paw Carrageenan Injection in Mice
Published on: November 15, 2024
Fabiane Y Yamacita-Borin1, Ana C Zarpelon2, Felipe A Pinho-Ribeiro2
1Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Av. Robert Koch 60, Londrina, Paraná, CEP 86038-350, Brazil.
Abstract:
Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-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 (0.5-5h 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 TNFα 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 TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation.
Insights
Superoxide anion triggers pain and inflammation, which is dependent on tumor necrosis factor-alpha (TNFα) signaling via TNFR1. Inhibiting TNFα/TNFR1 signaling reduces oxidative stress and pain, clarifying their interrelation.
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- Tumor necrosis factor-alpha (TNFα) and superoxide anion production are key mediators of inflammation and pain.
- Understanding the interplay between TNFα and superoxide anion in pain signaling is crucial for developing effective analgesics.
Purpose of the Study:
- To investigate if superoxide anion-induced pain relies on TNFα signaling.
- To determine the role of superoxide anion in TNFα-induced hyperalgesia.
- To elucidate the interrelation between TNFα and superoxide anion in pain.
Main Methods:
- Intraplantar injection of a superoxide anion donor (potassium superoxide) in wild-type mice.
- Assessment of mechanical hyperalgesia, neutrophil recruitment (myeloperoxidase activity), and pain-like behaviors.
- Utilized tumor necrosis factor receptor 1-deficient (TNFR1-/-) mice and etanercept treatment.
- Administered Apocynin (NADPH oxidase inhibitor) or Tempol (superoxide dismutase mimetic).
Main Results:
- Superoxide anion donor induced hyperalgesia, neutrophil recruitment, and pain behaviors in wild-type mice.
- TNFR1 deficiency and etanercept treatment inhibited superoxide anion-induced pain and oxidative stress.
- Apocynin or Tempol treatment attenuated TNFα-induced hyperalgesia and neutrophil recruitment.
Conclusions:
- TNFα/TNFR1 signaling is critical for superoxide anion-induced pain.
- TNFα/TNFR1 signaling amplifies superoxide anion-induced oxidative stress, sustaining pain and inflammation.
- Targeting the TNFα/superoxide anion pathway offers a potential strategy for pain management.
Related Concept Videos
Nociception
Analgesia and Pain Management

