Roles of reactive oxygen and nitrogen species in pain - PubMed (original) (raw)

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Roles of reactive oxygen and nitrogen species in pain

Daniela Salvemini et al. Free Radic Biol Med. 2011.

Abstract

Peroxynitrite (PN; ONOO⁻) and its reactive oxygen precursor superoxide (SO; O₂•⁻) are critically important in the development of pain of several etiologies including pain associated with chronic use of opiates such as morphine (also known as opiate-induced hyperalgesia and antinociceptive tolerance). This is now an emerging field in which considerable progress has been made in terms of understanding the relative contributions of SO, PN, and nitroxidative stress in pain signaling at the molecular and biochemical levels. Aggressive research in this area is poised to provide the pharmacological basis for development of novel nonnarcotic analgesics that are based upon the unique ability to selectively eliminate SO and/or PN. As we have a better understanding of the roles of SO and PN in pathophysiological settings, targeting PN may be a better therapeutic strategy than targeting SO. This is because, unlike PN, which has no currently known beneficial role, SO may play a significant role in learning and memory. Thus, the best approach may be to spare SO while directly targeting its downstream product, PN. Over the past 15 years, our team has spearheaded research concerning the roles of SO and PN in pain and these results are currently leading to the development of solid therapeutic strategies in this important area.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1

Fig. 1. Superoxide and peroxynitrite are targets for novel pain therapy

Superoxide (O2·−) and peroxynitrite (ONOO−) are key mediators in the development of peripheral and central sensitization of the various pain etiologies. The use of superoxide-dismutase mimetics (SODm, i.e. SC-72325) and peroxynitrite decomposition catalysts (PNDCs, i.e. FeTMPyP) reduce nitroxidative stress and attenuate the development of peripheral and central sensitization; providing promising novel therapy for chronic pain management.

Fig. 2

Fig. 2. Peroxynitrite-reinforced superoxide production in central sensitization: two feed forward mechanisms

Two major sites of superoxide (O2·−) production, NADPH oxidase and mitochondrial respiration, are active in the development of central sensitization. Peroxynitrite (ONOO−) formed from NADPH oxidase- and mitochondrial-derived superoxide nitrates and inactivates the manganese SOD (MnSOD) enzyme preventing the removal of mitochondrial-derived superoxide. Peroxynitrite enhances protein kinase C (PKC) activity and, in turn, enhances translocation of NADPH oxidase regulatory subunits to the membrane to increase the NADPH oxidase-derived superoxide production. Combined, these two mechanisms amplify superoxide-derived peroxynitrite formation leading to the development of central sensitization.

Fig. 3

Fig. 3. The role of peroxynitrite in glutamatergic homeostasis and signaling

Peroxynitrite (ONOO−) enhances glutamatergic signaling through nitration and activation of NMDARs and the protein kinases responsible for NMDAR activation. Peroxynitrite further enhances glutamatergic signaling by nitrating and inactivating the glutamate transporters (GLT-1, GLAST, and EAAC1) that remove glutamate (Glu) from the synapse and extrasynaptic regions and glutamine synthetase (GS) that converts glutamate, ammonia and ATP to glutamine, which is then taken back up by the neurons via the glutamine transporter. Nitration and inactivation of these enzymes results in toxic levels of glutamate and activation of neuroimmune responses. Inactivation of GS may also lead to increase ammonia levels that can inhibit glutamate transport. In addition to glutamate uptake, EAAC1 transports cysteine (Cys) into the neuron a process that is key in the biosynthesis of glutathione (GSH), a major cellular antioxidant. Compromised Cys transport by nitrated EAAC1 could lead to increased neuronal nitroxidative stress.

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