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Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity

jbzy513 添加于 2010-1-12 22:03 | 1745 次阅读 | 0 个评论

作者
Ndengele MM, Cuzzocrea S, Esposito E, Mazzon E, Di Paola R, Matuschak GM, Salvemini D
摘要
Peroxynitrite (ONOO(-)), the reaction product of the interaction between superoxide (O(2)(*-)) 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 O(2)(*-) (1 microM) led to the development of thermal hyperalgesia associated with a profound localized inflammatory response. Both events were blocked by L-NAME (N(G)-nitro-L-arginine methyl ester, 3-30 mg/kg), a nitric oxide synthase inhibitor, or by FeTM-4-PyP(5+) [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 O(2)(*-) 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 microM) similarly led to inflammatory hyperalgesia. ONOO(-) generated by the interaction between exogenous administration of O(2)(*-) and endogenous *NO, or provided by direct injection of ONOO(-), activated the transcription factor NF-kappaB 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) E(2) antibody (200 microg). In another established model of inflammation-related hyperalgesia by intraplantar injection of carrageenan in rats, inhibition of ONOO(-) with FeTM-4-PyP(5+) (3-30 mg/kg) inhibited the development of hyperalgesia and the release of PGE(2) in paw tissue exudates. Furthermore, FeTM-4-PyP(5+) 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-PGE(2) 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.
详细资料
- 关键词: Animals; Carrageenan; Cyclooxygenase 1/*physiology; Cyclooxygenase 2/*physiology; Cyclooxygenase Inhibitors/pharmacology; Drug Synergism; Edema/drug therapy; Hot Temperature; Hyperalgesia/chemically induced; Indomethacin/pharmacology; Male; Metalloporphyrins/pharmacology; NF-kappa B/metabolism; Nitrobenzenes/pharmacology; Pain/chemically induced/*physiopathology; Peroxynitrous Acid; Rats; Rats, Sprague-Dawley; Sulfonamides/pharmacology
- 文献种类:期刊
- 期刊名称: The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
- 期刊缩写: FASEB J
- 期卷页: 2008年第22卷第9期 3154-3164页
- 地址: 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
- ISBN: 1530-6860
- 备注:PMID:18497304
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