title: Hydrogen peroxide is a novel mediator of inflammatory hyperalgesia, acting via transient receptor potential vanilloid 1-dependent and independent mechanisms.
abstract: Inflammatory diseases associated with pain are often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Recently, there has been considerable interest in the role of reactive oxygen species (ROS) in inflammatory disease, but little is known of the role of hydrogen peroxide (H(2)O(2)) in hyperalgesia. In the present study, intraplantar injection of H(2)O(2)-induced a significant dose- and time-dependent mechanical and thermal hyperalgesia in the mouse hind paw, with increased c-fos activity observed in the dorsal horn of the spinal cord. H(2)O(2) also induced significant nociceptive behavior such as increased paw licking and decreased body liftings. H(2)O(2) levels were significantly raised in the carrageenan-induced hind paw inflammation model, showing that this ROS is produced endogenously in a model of inflammation. Moreover, superoxide dismutase and catalase significantly reduced carrageenan-induced mechanical and thermal hyperalgesia, providing evidence of a functionally significant endogenous role. Thermal, but not mechanical, hyperalgesia in response to H(2)O(2) (i.pl.) was longer lasting in TRPV1 wild type mice compared to TRPV1 knockouts. It is unlikely that downstream lipid peroxidation was increased by H(2)O(2). In conclusion, we demonstrate a notable effect of H(2)O(2) in mediating inflammatory hyperalgesia, thus highlighting H(2)O(2) removal as a novel therapeutic target for anti-hyperalgesic drugs in the clinic.
authors.affiliation: Pharmaceutical Science Research Division, Franklin-Wilkins Building, King's College London, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK. julie.keeble@kcl.ac.uk
authors.forename: Julie Elizabeth
authors.initials: JE
authors.lastname: Keeble
authors.forename: Jennifer Victoria
authors.initials: JV
authors.lastname: Bodkin
authors.forename: Lihuan
authors.initials: L
authors.lastname: Liang
authors.forename: Rachel
authors.initials: R
authors.lastname: Wodarski
authors.forename: Meirion
authors.initials: M
authors.lastname: Davies
authors.forename: Elizabeth Soares
authors.initials: ES
authors.lastname: Fernandes
authors.forename: Carly de Faria
authors.initials: Cde F
authors.lastname: Coelho
authors.forename: Fiona
authors.initials: F
authors.lastname: Russell
authors.forename: Rabea
authors.initials: R
authors.lastname: Graepel
authors.forename: Marcelo Nicolas
authors.initials: MN
authors.lastname: Muscara
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
authors.forename: Susan Diana
authors.initials: SD
authors.lastname: Brain
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002351:Carrageenan; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology / Q000473:pathology; D005260:Female; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000009:adverse effects / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism; D050916:TRPV Cation Channels / Q000172:deficiency / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
chemical_list: D016877:Oxidants; D016760:Proto-Oncogene Proteins c-fos; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D002351:Carrageenan; D006861:Hydrogen Peroxide