Abstract
The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10–100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO2, 30 μg). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNFα, IL-1β, IL-10, COX-2, preproET-1, gp91phox, Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO2-induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO2 were successfully inhibited by tempol. KO2-induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain.
Highlights
Superoxide dismutase (SOD) is an antioxidant enzyme that regulates the levels of reactive oxygen species such as superoxide anion (O2∙−) under basal conditions in tissue metabolism and health [1, 2]
KO2 induced mechanical hyperalgesia (Figure 1(a)) and thermal hyperalgesia (Figure 1(b)) and paw edema (Figure 1(c)) between 1 and 5 h after injection compared to the vehicle group, which were inhibited by tempol in a time- and dose-dependent manner
Tempol treatment inhibited carrageenan- (Figures 8(a) and 8(b)) and complete Freund’s adjuvant (CFA)- (Figures 8(c) and 8(d)) induced mechanical hyperalgesia and thermal hyperalgesia between 1 and 5 h and between 1 and 7 days, respectively. These results indicate that the analgesic effect of tempol is not limited to superoxide anion-triggered hyperalgesia, but it is relevant in classical models of inflammatory pain such as carrageenan and CFA
Summary
Superoxide dismutase (SOD) is an antioxidant enzyme that regulates the levels of reactive oxygen species such as superoxide anion (O2∙−) under basal conditions in tissue metabolism and health [1, 2]. After tissue injury and/or infections, neutrophils are initially recruited following inflammatory and chemotactic signals, which include the inflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF) [5] as well as reactive oxygen species themselves [6]. After being recruited into the inflammatory focus, neutrophils are activated by these signals, including the activation of the socalled respiratory burst represented by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase membranebound enzyme complex production of superoxide anion in neutrophils. This scenario characterized by the exacerbation of superoxide anion production propagates the inflammatory response resulting in sensitization of primary nociceptive
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