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* Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA;
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy; and
IRCCS Centro Neurolesi "Bonino-Pulejo" Messina, Messina, Italy
2Correspondence: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 1402 S. Grand Blvd., Deslodge Towers, 7th Floor, Saint Louis University School of Medicine, St. Louis, MO 63104-1028, USA. E-mail: salvemd{at}slu.edu
Peroxynitrite (ONOO–), the reaction product of the interaction between superoxide (O2·–) and nitric oxide (·NO), is a potent proinflammatory and cytotoxic nitrooxidative species. Its role as a mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) is not known. In light of the known proinflammatory properties of ONOO–, our study addressed its potential involvement in the development of hyperalgesia associated with tissue damage and inflammation. Intraplantar injection in rats of the ONOO– precursor O2·– (1 µM) led to the development of thermal hyperalgesia associated with a profound localized inflammatory response. Both events were blocked by L-NAME (NG-nitro-L-arginine methyl ester, 3–30 mg/kg), a nitric oxide synthase inhibitor, or by FeTM-4-PyP5+ [Fe(III)5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, 3–30 mg/kg], an ONOO– decomposition catalyst. These results suggested that locally synthesized ONOO– produced in situ by O2·– and ·NO is key in the development of inflammatory hyperalgesia. The direct link between ONOO– and hyperalgesia was further supported by demonstrating that intraplantar injection of soluble ONOO– itself (1 µM) similarly led to inflammatory hyperalgesia. ONOO– generated by the interaction between exogenous administration of O2·– and endogenous ·NO, or provided by direct injection of ONOO–, activated the transcription factor NF-
B in paw tissues, enhancing expression of the inducible but not the constitutive cyclooxygenase enzyme (COX-2 and COX-1, respectively). ONOO–-mediated hyperalgesia was blocked in a dose-dependent manner by intraperitoneal injections of indomethacin (10 mg/kg), a nonselective COX-1/COX-2 inhibitor, or NS398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 10 mg/kg] a selective COX-2 inhibitor, as well as by an anti-prostaglandin (PG) E2 antibody (200 µg). In another established model of inflammation-related hyperalgesia by intraplantar injection of carrageenan in rats, inhibition of ONOO– with FeTM-4-PyP5+ (3–30 mg/kg) inhibited the development of hyperalgesia and the release of PGE2 in paw tissue exudates. Furthermore, FeTM-4-PyP5+ synergized with indomethacin and NS397 (1–10 mg/kg) to block both hyperalgesia and edema. Taken together, these data show for the first time that ONOO– is a potent mediator of inflammation-derived hyperalgesia operating via the COX-to-PGE2 pathway. These results provide a pharmacological rationale for the development of inhibitors of peroxynitrite biosynthesis as novel nonnarcotic analgesics. The broad implications of our study are that dual inhibition of both ONOO– formation and COX activity may provide an alternative therapeutic approach to the management of pain: effective analgesia with reduced side-effects typically associated with the use of COX inhibitors.—Ndengele, M. N., Cuzzocrea, S., Esposito, E., Mazzon, E., Di Paola, R., Matuschak, G. M., Salvemini, D. Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity.
Key Words: superoxide • nitric oxide • PGE2 • COX-1 • COX-2 • hyperalgesia
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