The key role of peroxynitrite in supraspinal nociceptive modulation during pathophysiological pain

Chronic pain is a complex pathophysiological state that affects millions of individuals. Therefore studies to determine the cause of chronic pain serve an important purpose. The objective of this dissertation was to investigate the role of peroxynitrite (PN), an oxidant and nitrating agent, in supraspinal descending facilitation of spinal nociception that drives chronic and persistent (pathophysiological) pain. The rostral ventromedial medulla (RVM) is capable of modulating spinal nociception. During pathophysiological pain the RVM engages descending facilitation which enhances spinal nociception and contributes to hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli. There are changes to the RVM microenvironment that contribute to descending facilitation that are similar to those that occur in the spinal cord during central sensitization, a putative underlying state that drives pathophysiological pain. As PN contributes to central sensitization, it is possible that PN also contributes to RVM descending facilitation. The data presented herein are the first to demonstrate the essential role of PN in the RVM during inflammatory and neuropathic pain.;Using well-described animal models for inflammatory (Hargreaves) and neuropathic (Bennett) pain, we investigated the contribution of RVM PN to thermal hyperalgesia and mechanical allodynia, respectively. First, the immunoreactivity of 3-nitrotyrosine (3-NT), a biomarker for PN formation and nitration, was examined at peak hyperalgesia. Additionally, the functional contribution of PN to RVM descending facilitation was investigated using therapeutic microinjections of a PN decomposition catalyst (PNDC). We also studied PN mediated negative regulation of opioids as an underlying mechanism that engages RVM descending facilitation. Finally, the role of PN in chronic neuropathic pain was tested using RVM microinjections of a PNDC.;The results of these studies provide a foundation for further elucidating the role of PN in the brain during pain states and support the hypothesis that PN is essential to RVM descending facilitation of spinal nociception during pathophysiological pain.;Keywords: pain; peroxynitrite; rostral ventromedial medulla (RVM); nociceptive modulation; descending inhibition; descending facilitation; nitroxidative stress; FeTMPyP; superoxide; nitric oxide; periaqueductal gray (PAG).