The role of reactive oxygen species (ROS) in persistent pain.

Pain is an important medical problem and has been the subject of intense study in recent years; however, we still do not understand many of the details of pain generation and analgesic mechanisms, particularly for persistent pain. This lack of sufficient understanding is a major stumbling block in the development of much better analgesic drugs. We now know that the mechanisms of chronic or persistent pain (such as pain associated with inflammation or nerve injury) are fundamentally different from those of acute pain (sometimes called nociceptive pain or physiological pain) (1–3). In acute pain, noxious stimuli are detected by nociceptors and the information is transmitted to the brain. The situation in persistent pain, however, involves the maintenance of peripheral and/or central sensitization (Figure 1). Peripheral sensitization is manifested by nociceptors such that they not only respond more vigorously to a suprathreshold stimulus but also the threshold needed for response is lowered. A common cause of peripheral sensitization is tissue inflammation. Central sensitization refers to a similar phenomenon occurring in pain-transmission neurons in the central nervous system (CNS), often in the dorsal horn of the spinal cord (1, 4, 5). Peripheral sensitization may lead to central sensitization, but central sensitization can be maintained with or without peripheral sensitization. N-methyl-D-aspartate (NMDA) receptors are thought to mediate central sensitization, and several different types of second messengers are involved in the cascade of changes that occur in the spinal cord (1–3, 5, 6). Reactive oxygen species (ROS) have been implicated in many degenerative neurological conditions, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and other brain dysfunctions ranging from brain injury to aging (7–13). In addition, oxidative stress is an important determinant of degenerative and painful pathological conditions in peripheral nerve fibers (14). Most of these studies, however, emphasize oxidative stress– induced cell death or degeneration. In contrast, I emphasize here the possibility that neurons that are less severely stressed survive but become dysfunctional and produce pain. Recently, Wang et al. reported that superoxide (SO), a type of ROS, mediates pain that accompanies inflammation (15). Their experimental results indicate that an application of a synthetic compound (M40403) that mimics the enzymatic function of superoxide dismutase (SOD), which breaks down SO, prevents development of inflammation and hyperalgesia after injection of an inflammatory agent into the rat paw. Furthermore, the SOD mimetic given after induction of inflammation also reduces developed hyperalgesia. These results suggest that SO participates in the nociceptive signaling cascade and in nociceptor sensitization. The authors propose, with some supporting data, that SOD is nitrated in inflammatory conditions and loses its function. Consequently, SO accumulates and high concentrations of SO combine with nitric oxide (NO) to form peroxynitrite. Peroxynitrite inhibits the catalytic function of SOD by nitrating the enzyme. The analgesic effect produced by M40403 treatment is not blocked by naloxone, indicating that opioids are not involved in mediating the analgesia. The results are encouraging for the development of non-steroidal and non-opioid analgesics. The essential part of this paper has been published elsewhere by the same authors at an earlier time (16). Therefore, although not a confirmation by independent investigators, the data published here confirm their earlier results; however, a few aspects of this paper are less than completely satisfactory. First, several important points are made with no quantitative data. For example, histological evidence of inflammation, immunohistochemical study for nitrotyrosine, and immunoprecipitation for manganese superoxide dismutase (MnSOD) are presented as single data points. Second, histological examination of the spinal cord for immunological staining should have been done in the dorsal horn, not on motor nuclei, to be more relevant. Nevertheless, this study provides experimental evidence supporting the strong analgesic action of an SOD mimetic on inflammatory pain. Although SO is an important ROS, there are other reactive oxygen–containing species that may play an important role in pain as well. In addition, there may be painful conditions other Viewpoint