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.