title: The superoxide anion donor, potassium superoxide, induces pain and inflammation in mice through production of reactive oxygen species and cyclooxygenase-2.
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.
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: N A
authors.initials: NA
authors.lastname: Maioli
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: A C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: S S
authors.initials: SS
authors.lastname: Mizokami
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: C
authors.initials: C
authors.lastname: Calixto-Campos
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: C F S
authors.initials: CF
authors.lastname: Guazelli
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: M S N
authors.initials: MS
authors.lastname: Hohmann
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: F A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: T T
authors.initials: TT
authors.lastname: Carvalho
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: M F
authors.initials: MF
authors.lastname: Manchope
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: C R
authors.initials: CR
authors.lastname: Ferraz
authors.affiliation: Centro de Ciências da Saúde, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: R
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, PR, Brasil.
authors.forename: W A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced; D006614:Hindlimb; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy; D008297:Male; D051379:Mice; D059226:Nociceptive Pain / Q000139:chemically induced* / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D009195:Peroxidase / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects; D013481:Superoxides / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D017382:Reactive Oxygen Species; D013481:Superoxides; C039316:potassium superoxide; D009195:Peroxidase; D051546:Cyclooxygenase 2