A newly identified role for superoxide in inflammatory pain.
Novel classes of pain-relieving molecules are needed to fill the void between nonsteroidal anti-inflammatory agents and narcotics. Our studies have identified superoxide as a novel mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) and have exposed potential pathways through which this radical modulates the hyperalgesic response. The role of superoxide in pain was elucidated using a superoxide dismutase mimetic, M40403 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand]. Intraplantar injection of carrageenan in rats led to time-dependent development of peripheral inflammation [measured parameters of inflammation included paw edema, cytokine release in the paw exudates, nitrotyrosine formation (a marker of peroxynitrite formation and oxidative stress), and poly-ADP-ribose-polymerase activation (the nuclear enzyme activated by superoxide/peroxynitrite)] and hyperalgesia. M40403 blocked all measured parameters of inflammation and hyperalgesia. Furthermore, when given therapeutically (2 h after the induction of hyperalgesia) either by intravenous or intrathecal administration, M40403 but not its inactive congener M40404 inhibited hyperalgesia with a rapid onset of action. Our results also show that, at the level of the spinal cord and time of peak hyperalgesia, endogenous manganese superoxide dismutase was nitrated and subsequently deactivated, losing its capacity to remove superoxide. The antihyperalgesic effects of M40403 were not reversed by naloxone excluding the potential involvement of an opiate pathway. Collectively, these studies have unraveled a critical role for superoxide in the nociceptive signaling cascade both peripherally and centrally. The discovery of this pathway opens a new therapeutic strategy for the development of novel nonnarcotic antihyperalgesic agents.
Department of Biological and Pharmacological Research, Metaphore Pharmaceuticals, 1910 Innerbelt Business Center Drive, St. Louis, MO 63114, USA.
Zhi-Qiang
ZQ
Wang
Frank
F
Porreca
Salvatore
S
Cuzzocrea
Karen
K
Galen
Richard
R
Lightfoot
Emanuela
E
Masini
Carolina
C
Muscoli
Vincenzo
V
Mollace
Michael
M
Ndengele
Harry
H
Ischiropoulos
Daniela
D
Salvemini
D000818:Animals; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008345:Manganese; D009942:Organometallic Compounds / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000502:physiology; D013481:Superoxides / Q000009:adverse effects* / Q000378:metabolism
D009942:Organometallic Compounds; D013481:Superoxides; C121876:imisopasem manganese; D008345:Manganese; D002351:Carrageenan; D013482:Superoxide Dismutase