Abstract
It is currently accepted that superoxide anion (O2 •−) is an important mediator in pain and inflammation. The role of superoxide anion in pain and inflammation has been mainly determined indirectly by modulating its production and inactivation. Direct evidence using potassium superoxide (KO2), a superoxide anion donor, demonstrated that it induced thermal hyperalgesia, as assessed by the Hargreaves method. However, it remains to be determined whether KO2 is capable of inducing other inflammatory and nociceptive responses attributed to superoxide anion. Therefore, in the present study, we investigated the nociceptive and inflammatory effects of KO2. The KO2-induced inflammatory responses evaluated in mice were: mechanical hyperalgesia (electronic version of von Frey filaments), thermal hyperalgesia (hot plate), edema (caliper rule), myeloperoxidase activity (colorimetric assay), overt pain-like behaviors (flinches, time spent licking and writhing score), leukocyte recruitment, oxidative stress, and cyclooxygenase-2 mRNA expression (quantitative PCR). Administration of KO2 induced mechanical hyperalgesia, thermal hyperalgesia, paw edema, leukocyte recruitment, the writhing response, paw flinching, and paw licking in a dose-dependent manner. KO2 also induced time-dependent cyclooxygenase-2 mRNA expression in the paw skin. The nociceptive, inflammatory, and oxidative stress components of KO2-induced responses were responsive to morphine (analgesic opioid), quercetin (antioxidant flavonoid), and/or celecoxib (anti-inflammatory cyclooxygenase-2 inhibitor) treatment. In conclusion, the well-established superoxide anion donor KO2 is a valuable tool for studying the mechanisms and pharmacological susceptibilities of superoxide anion-triggered nociceptive and inflammatory responses ranging from mechanical and thermal hyperalgesia to overt pain-like behaviors, edema, and leukocyte recruitment.
Highlights
Inflammation-related events such as edema, leukocyte recruitment, and pain are important for the protection of organisms, but excessive and persistent inflammation leads to tissue damage, chronic pain, and organ dysfunction
All doses of KO2 induced statistically significant mechanical hyperalgesia compared to the control group at all time points, except the dose quantitative polymerase chain reaction (qPCR) Paw skin samples were homogenized in TRIzol reagent (Life Technologies, USA), and total RNA was isolated according to the manufacturer’s instructions
Complementary DNA was reversely transcribed from 2 mg of total RNA, and qPCR was performed for 50 cycles on a LightCycler Nano Instrument (Roche, Switzerland)
Summary
Inflammation-related events such as edema, leukocyte recruitment, and pain are important for the protection of organisms, but excessive and persistent inflammation leads to tissue damage, chronic pain, and organ dysfunction. Oxidative stress is an important component of pain and inflammation. Antioxidants such as the flavonoid, quercetin, inhibit overt pain-like behavior, carrageenan-induced mechanical hyperalgesia, and paw edema by diminishing interleukin-1b production and reducing glutathione (GSH) depletion [2]. Quercetin inhibits leukocyte recruitment [3] and acetic acid-induced colitis in mice [4]. This is a consistent effect observed with antioxidants [5,6]. Quercetin is considered to be a standard antioxidant flavonoid, because it presents all the structural groups related to antioxidant activity possessed by this class of molecules [2,3,4]
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