Hydrogen peroxide is a novel mediator of inflammatory hyperalgesia, acting via transient receptor potential vanilloid 1-dependent and independent mechanisms.
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.
Keeble
Julie Elizabeth
JE
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
Bodkin
Jennifer Victoria
JV
Liang
Lihuan
L
Wodarski
Rachel
R
Davies
Meirion
M
Fernandes
Elizabeth Soares
ES
Coelho
Carly de Faria
Cde F
Russell
Fiona
F
Graepel
Rabea
R
Muscara
Marcelo Nicolas
MN
Malcangio
Marzia
M
Brain
Susan Diana
SD
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
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