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

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 3

When compared with naive group, vehicle group did not lead to nitration of MnSOD or CuZnSOD in dorsal horn tissues as measured by immunoprecipitation.

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When compared with naive group, vehicle group did not lead to nitration ...
On the other hand, acute administration of morphine in animals that received repeated administration of morphine led to significant nitration of MnSOD (A) but not CuZnSOD (D). (A) Coadministration of morphine over 4 days with l-NAME (10 mg/kg/d), MnTBAP3– (10 mg/kg/d), or FeTM-4-PyP5+ (30 mg/kg/d) prevented MnSOD nitration. (B) Posttranslational nitration of MnSOD led to functional enzymatic inactivation as evidenced by loss of its catalytic activity to dismute O2– as measured spectrophotometrically. Coadministration of morphine with l-NAME (10 mg/kg/d), MnTBAP3– (10 mg/kg/d), or FeTM-4-PyP5+ (30 mg/kg/d) restored the enzymatic activity of MnSOD. (E) The enzymatic activity of CuZnSOD was not affected. When compared with the naive or vehicle group, repeated administration of morphine did not change the total amount of MnSOD (C) or CuZnSOD (F) in dorsal horn tissues as measured by Western blotting analysis. Gels shown in A, C, D, and F are representative of gel results obtained from 6 animals. A composite (n = 6) of the densitometry data resulting from these experiments is shown in Table 1. *P < 0.001 for morphine alone versus vehicle; †P < 0.001 for morphine plus drug versus morphine alone.