Roles of reactive oxygen and nitrogen species in pain

Abstract

Peroxynitrite (PN, ONOO−) and its reactive oxygen precursor superoxide (SO, O2·−), are critically important in the development of pain of several etiologies including in the development of 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 contribution 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 non-narcotic analgesics that are based upon the unique ability to selectively eliminate SO and/or PN. As we have a better understanding of the role of SO and PN in pathophysiological settings, targeting PN may be a better therapeutic strategy than targeting SO. This is due to the fact that unlike PN, which has no currently known beneficial role, SO may play a significant role in learning and memory [1]. Thus, the best approach may be to spare SO while directly targeting its downstream product, PN. Over the last 15 years, our team has spearheaded research concerning the roles of SO/PN in pain and these results are currently leading to the development of solid therapeutic strategies in this important area.

Targeting the Overproduction of Peroxynitrite for the Prevention and Reversal of Paclitaxel-Induced Neuropathic Pain

“…PN-mediated nitration and inactivation of MnSOD is an additional significant source in maintaining elevated levels of PN at pathophysiological sites (Macmillan-Crow and Cruthirds, 2001). The occurrence of this nitrated MnSOD in the spinal cord has been also linked to development of central sensitization in several experimental models of pain (for review, see Salvemini et al, 2011). We now show that this process is operative in paclitaxel-induced neuropathic pain as shown in Figure 4.…”

“…The fact that Cu,ZnSOD activity was unaffected is consistent with the fact that PN does not affect the catalytic activity of Cu,ZnSOD (Smith et al, 1992). Viable sources for PN production include neurons and/or activated glia, since both generate NO and SO (for review, see Salvemini et al, 2011). Pinpointing the cell population(s) in vivo responsible for PN production is difficult given the membrane diffusability of PN to allow post-translational nitration in adjacent cells (Ferrer-Sueta and Radi, 2009).…”

“…Peroxynitrite (PN), the reaction product of superoxide (SO) and nitric oxide (NO) (Beckman et al, 1990), is a potent proinflammatory and pronociceptive species implicated in pain of several etiologies (for review, see Salvemini et al, 2011). In these settings, two glial pathways underlie PNЈs effects in spinal cord: increased TNF-␣ and IL-1␤ contributing to hypersensitivity in dorsal horn neurons (for review, see DeLeo and Yezierski, 2001;Watkins et al, 2001;Milligan and Watkins, 2009) and posttranslational nitration of the glutamate transporter (GT), GLT-1, and glutamine synthetase (GS), key regulators of optimal synaptic glutamate homeostasis (Kugler, 1993).…”

“…Moreover, the lack of oral bioavailability can restrict their chronic use (for review, see Salvemini et al, 2011). Evidence also indicates the importance of SO in learning and memory (Massaad and Klann, 2010), while PN has no known benefit.…”

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…Because pain can persist long after the initial injury has been resolved, it causes major health problems (Basbaum et al, 2009;Schmidtko et al, 2010). Accumulating evidence suggests that reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ) and superoxide (O 2 Ϫ ), and the active superoxide byproduct peroxynitrite essentially contribute to the sensitization during persistent pain (Salvemini et al, 2011). Accordingly, the nociceptive behavior was inhibited in animal models of pain after systemic or intrathecal administration of antioxidants, free radical scavengers, and peroxynitrite-decomposition catalysts (Kim et al, 2004;Wang et al, 2004;Lu et al, 2011;Yowtak et al, 2011;Janes et al, 2012).…”