Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice
Open Access
- 1 November 2007
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 117 (11), 3530-3539
- https://doi.org/10.1172/jci32420
Abstract
Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, often because chronic opiate therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing side effects. The mechanisms leading to tolerance are poorly understood. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice was consistently associated with the appearance of several tyrosine-nitrated proteins in the dorsal horn of the spinal cord, including the mitochondrial isoform of superoxide (O2–) dismutase, the glutamate transporter GLT-1, and the enzyme glutamine synthase. Furthermore, antinociceptive tolerance was associated with increased formation of several proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear factor poly(ADP-ribose) polymerase. Inhibition of NO synthesis or removal of O2– blocked these biochemical changes and inhibited the development of tolerance, pointing to peroxynitrite (ONOO–), the product of the interaction between O2– and NO, as a signaling mediator in this setting. Indeed, coadministration of morphine with the ONOO– decomposition catalyst, Fe(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, blocked protein nitration, attenuated the observed biochemical changes, and prevented the development of tolerance in a dose-dependent manner. Collectively, these data suggest a causal role for ONOO– in pathways culminating in antinociceptive tolerance to opiates. Peroxynitrite (ONOO–) decomposition catalysts may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.Keywords
This publication has 76 references indexed in Scilit:
- Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioidsBrain, Behavior, and Immunity, 2006
- Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the ratHepatology, 2005
- Protein S-nitrosylation: purview and parametersNature Reviews Molecular Cell Biology, 2005
- Antinociceptive and nociceptive actions of opioidsJournal of Neurobiology, 2004
- Superoxide-mediated nitration of spinal manganese superoxide dismutase: a novel pathway in N -methyl-d-aspartate-mediated hyperalgesiaPain, 2004
- On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studiesBritish Journal of Pharmacology, 2003
- Peroxynitrite Is an Essential Component of Cytokines Production Mechanism in Human Monocytes through Modulation of Nuclear Factor-κB DNA Binding ActivityJournal of Biological Chemistry, 2002
- NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticityBrain Research Reviews, 1999
- The opioid–cytokine connectionJournal of Neuroimmunology, 1998
- Peroxynitrite Inhibits Glutamate Transporter SubtypesJournal of Biological Chemistry, 1996