Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice.
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.
Departamento 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.
Fabiane Y
FY
Yamacita-Borin
Departamento 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.
Ana C
AC
Zarpelon
Departamento 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.
Felipe A
FA
Pinho-Ribeiro
Departamento 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.
Victor
V
Fattori
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil.
Jose C
JC
Alves-Filho
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil.
Fernando Q
FQ
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil.
Thiago M
TM
Cunha
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Av. Robert Koch 60, Londrina, Paraná, CEP 86038-350, Brazil.
Rubia
R
Casagrande
Departamento 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. Electronic address: waverri@uel.br.
Waldiceu A
WA
Verri
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000068800:Etanercept / Q000494:pharmacology; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D018384:Oxidative Stress; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D009195:Peroxidase / Q000378:metabolism; D010812:Physical Stimulation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D014110:Touch; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C039316:potassium superoxide; D009195:Peroxidase; D000068800:Etanercept
Hyperalgesia; Inflammation; Oxidative stress; Superoxide anion; TNFR1; TNFα