Reactive nitroxidative species and nociceptive processing: determining the roles for nitric oxide, superoxide, and peroxynitrite in pain

Pain is a multidimensional perception and is modified at distinct regions of the neuroaxis. During enhanced pain, neuroplastic changes occur in the spinal and supraspinal nociceptive modulating centers and may result in a hypersensitive state termed central sensitization, which is thought to contribute to chronic pain states. Central sensitization culminates in hyperexcitability of dorsal horn nociceptive neurons resulting in increased nociceptive transmission and pain perception. This state is associated with enhanced nociceptive signaling, spinal glutamate-mediated N-methyl-d-aspartate receptor activation, neuroimmune activation, nitroxidative stress, and supraspinal descending facilitation. The nitroxidative species considered for their role in nociception and central sensitization include nitric oxide (NO), superoxide ( \text O₂^·-{\text {O}_2}^{{\cdot }^{-}}), and peroxynitrite (ONOO⁻). Nitroxidative species are implicated during persistent but not normal nociceptive processing. This review examines the role of nitroxidative species in pain through a discussion of their contributions to central sensitization and the underlying mechanisms. Future directions for nitroxidative pain research are also addressed. As more selective pharmacologic agents are developed to target nitroxidative species, the exact role of nitroxidative species in pain states will be better characterized and should offer promising alternatives to available pain management options.