Supraspinal peroxynitrite modulates pain signaling by suppressing the endogenous opioid pathway

Joshua W. Little, Zhoumou Chen, Timothy Doyle, Frank Porreca, Mahsa Ghaffari, Leesa Bryant, William L. Neumann, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Peroxynitrite (PN, ONOO -) is a potent oxidant and nitrating agent that contributes to pain through peripheral and spinal mechanisms, but its supraspinal role is unknown. We present evidence here that PN in the rostral ventromedial medulla (RVM) is essential for descending nociceptive modulation in rats during inflammatory and neuropathic pain through PN-mediated suppression of opioid signaling. Carrageenan-induced thermal hyperalgesia was associated with increased 3-nitrotyrosine (NT), a PN biomarker, in the RVM. Furthermore, intra-RVM microinjections of the PN decomposition catalyst Fe(III)-5,10,15,20-tetrakis(N-methyl-pyridinium-4-yl)porphyrin (FeTMPyP 5+) dose-dependently reversed this thermal hyperalgesia. These effects of FeTMPyP 5+ were abrogated by intraRVM naloxone, implicating potential interplay between PN and opioids. In support, we identified NT colocalization with the endogenous opioid enkephalin (ENK) in the RVM during thermal hyperalgesia, suggesting potential in situ interactions. To address the functional significance of such interactions, we exposed methionine-enkephalin (MENK) to PN and identified the major metabolite, 3-nitrotyrosine-methionine-sulfoxide (NSO)-MENK, using liquid chromatography-mass spectrometry. Next, we isolated, purified, and tested NSO-MENK for opioid receptor binding affinity and analgesic effects. Compared to MENK, this NSO-MENK metabolite lacked appreciable binding affinity for, δ, μ and κopioid receptors. Intrathecal injection of NSO-MENK in rats did not evoke antinociception, suggesting that PN-mediated chemical modifications of ENK suppress opioid signaling. When extended to chronic pain, intra-RVM FeTMPyP 5+ produced naloxone-sensitive reversal of mechanical allodynia in rats following chronic constriction injury of the sciatic nerve. Collectively, our data reveal the central role of PN in RVM descending facilitation during inflammatory and neuropathic pain potentially through anti-opioid activity.

Original languageEnglish (US)
Pages (from-to)10797-10808
Number of pages12
JournalJournal of Neuroscience
Issue number32
StatePublished - Aug 8 2012

ASJC Scopus subject areas

  • General Neuroscience


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