Supraspinal Peroxynitrite Modulates Pain Signaling by Suppressing the Endogenous Opioid Pathway
| Autor: | Timothy M. Doyle, Frank Porreca, Mahsa Mohammadebrahim Ghaffari, William L. Neumann, Leesa Bryant, Joshua W. Little, Zhoumou Chen, Daniela Salvemini |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Microinjections Enkephalin Metalloporphyrins Enkephalin Methionine Pain (+)-Naloxone Pharmacology Carrageenan Article Rats Sprague-Dawley Radioligand Assay Peroxynitrous Acid Opioid Receptor Binding Glial Fibrillary Acidic Protein medicine Animals Humans Injections Spinal Cell Line Transformed Pain Measurement Endogenous opioid Neurons Analysis of Variance Medulla Oblongata CD11b Antigen Dose-Response Relationship Drug Chemistry General Neuroscience Chronic pain Electrochemical Techniques medicine.disease Rats Disease Models Animal Opioid Peptides Opioid Hyperalgesia Phosphopyruvate Hydratase Anesthesia Chronic Disease Neuropathic pain Tyrosine Rostral ventromedial medulla Neuroglia Chromatography Liquid Protein Binding Signal Transduction medicine.drug |
| Zdroj: | The Journal of Neuroscience. 32:10797-10808 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.6345-11.2012 |
| Popis: | 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 (FeTMPyP5+) dose-dependently reversed this thermal hyperalgesia. These effects of FeTMPyP5+were abrogated by intra-RVM 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 potentialin situinteractions. 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 κ opioid 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 FeTMPyP5+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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|