Superoxide signaling in pain is independent of nitric oxide signaling

Two reactive oxygen species (ROS), nitric oxide (NO) and superoxide (O2), contribute to persistent pain. Using three different animal models where ROS mediate pain, this study examined whether NO and O2 converge to peroxynitrite (ONOO) or whether each has an independent signaling pathway to produce hyperalgesia. The hyperalgesia after spinal nerve ligation was attenuated by removing O2 by TEMPOL or inhibiting NO production by L-NAME, but not by removing peroxynitrite with FeTMPyP. Nitric oxide-induced hyperalgesia was not affected by removing O2 but was reduced by a guanyl cyclase inhibitor. Superoxide-induced hyperalgesia was not affected by inhibiting NO production but was suppressed by a protein kinase C inhibitor. The data suggest that NO and O2 operate independently to generate pain.