TY - JOUR T1 - A Newly Identified Role for Superoxide in Inflammatory Pain JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 869 LP - 878 DO - 10.1124/jpet.103.064154 VL - 309 IS - 3 AU - Zhi-Qiang Wang AU - Frank Porreca AU - Salvatore Cuzzocrea AU - Karen Galen AU - Richard Lightfoot AU - Emanuela Masini AU - Carolina Muscoli AU - Vincenzo Mollace AU - Michael Ndengele AU - Harry Ischiropoulos AU - Daniela Salvemini Y1 - 2004/06/01 UR - http://jpet.aspetjournals.org/content/309/3/869.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -