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Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice
Carolina Muscoli, … , George M. Matuschak, Daniela Salvemini
Carolina Muscoli, … , George M. Matuschak, Daniela Salvemini
Published November 1, 2007
Citation Information: J Clin Invest. 2007;117(11):3530-3539. https://doi.org/10.1172/JCI32420.
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Research Article

Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice

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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.

Authors

Carolina Muscoli, Salvatore Cuzzocrea, Michael M. Ndengele, Vincenzo Mollace, Frank Porreca, Francesca Fabrizi, Emanuela Esposito, Emanuela Masini, George M. Matuschak, Daniela Salvemini

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Figure 1

On day 5 acute injection of morphine (3 mg/kg) in animals that received saline over 4 days (vehicle group) produced a significant antinociceptive response when compared with responses observed in animals that received an equivalent volume of saline (naive group).

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On day 5 acute injection of morphine (3 mg/kg) in animals that received ...
On the other hand, a significant loss to the antinociceptive effect of the acute injection of morphine was observed in animals that received repeated administration of morphine over 4 days (morphine group; Mor). Coadministration of morphine over 4 days with (A) l-NAME (1–10 mg/kg/d), (B) MnTBAP3– (1–10 mg/kg/d), or (C) FeTM-4-PyP5+ (3–30 mg/kg/d) inhibited the development of tolerance in a dose-dependent manner. Results are expressed as mean ± SEM for 12 animals. °P < 0.001 for vehicle versus naive; *P < 0.001 for morphine versus vehicle; †P < 0.001 for morphine plus drug versus morphine alone.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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