J Clin Invest. 2007 Nov;117(11):3530-9. Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. Muscoli C, Cuzzocrea S, Ndengele MM, Mollace V, Porreca F, Fabrizi F, Esposito E, Masini E, Matuschak GM, Salvemini D. Source Faculty of Pharmacy, University of Catanzaro Magna Graecia, Roccelletta di Borgia, Catanzaro, Italy. 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. Comment in J Clin Invest. 2007 Nov;117(11):3185-7.

Therapeutic manipulation of peroxynitriteattenuates the development of opiate-inducedantinociceptive tolerance in mice / C.Muscoli; S.Cuzzocrea; MM. Ndengele; V.Mollace; F.Porreca; F.Fabrizi; E.Esposito; E.Masini; GM. Matuschak; D.Salvemini. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - STAMPA. - 117:(2007), pp. 3530-3539. [10.1172/JCI32420]

Therapeutic manipulation of peroxynitriteattenuates the development of opiate-inducedantinociceptive tolerance in mice

FABRIZI, FRANCESCA;MASINI, EMANUELA;
2007

Abstract

J Clin Invest. 2007 Nov;117(11):3530-9. Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. Muscoli C, Cuzzocrea S, Ndengele MM, Mollace V, Porreca F, Fabrizi F, Esposito E, Masini E, Matuschak GM, Salvemini D. Source Faculty of Pharmacy, University of Catanzaro Magna Graecia, Roccelletta di Borgia, Catanzaro, Italy. 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. Comment in J Clin Invest. 2007 Nov;117(11):3185-7.
2007
117
3530
3539
C.Muscoli; S.Cuzzocrea; MM. Ndengele; V.Mollace; F.Porreca; F.Fabrizi; E.Esposito; E.Masini; GM. Matuschak; D.Salvemini
File in questo prodotto:
File Dimensione Formato  
Therapeutic manipulation of peroxynitrite.pdf

Accesso chiuso

Tipologia: Versione finale referata (Postprint, Accepted manuscript)
Licenza: Tutti i diritti riservati
Dimensione 828.35 kB
Formato Adobe PDF
828.35 kB Adobe PDF   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/600211
Citazioni
  • ???jsp.display-item.citation.pmc??? 73
  • Scopus 126
  • ???jsp.display-item.citation.isi??? 123
social impact