Anti-superoxide and anti-peroxynitrite strategies in pain suppression

Abstract

Superoxide (SO, O(2)·(-)) and its reaction product peroxynitrite (PN, ONOO(-)) have been shown to be important in the development of pain of several etiologies. While significant progress has been made in teasing out the relative contribution of SO and PN peripherally, spinally, and supraspinally during the development and maintenance of central sensitization and pain, there is still a considerable void in our understanding. Further research is required in order to develop improved therapeutic strategies for selectively eliminating SO and/or PN. Furthermore, it may be that PN is a more attractive target, in that unlike SO it has no currently known beneficial role. Our group has been at the forefront of research concerning the role of SO and PN in pain, and our current findings have led to the development of two new classes of orally active catalysts which are selective for PN decomposition while sparing SO. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Fig. 1. Peroxynitrite modulates central sensitization through a variety of mechanisms

Peroxynitrite (PN) formed within the periphery, the spinal cord, and in supraspinal areas modulates central sensitization associated with pain of several etiologies. Pathways known to be potentially impacted as a result of overt formation of PN are depicted.

Fig. 2. Therapeutic strategies targeting peroxynitrite

Targeting peroxynitrite (PN) with superoxide dismutase mimetics (SODm), peroxynitrite decomposition catalysts (PNDCs) which also have SODm activity, or with SO-sparing PNDCs (e.g. SRI6, SRI110) may provide a promising novel therapy for pain management.