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975897 
Journal Article 
Abstract 
Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite mediated pathways 
Salvemini, D; Batinic-Haberle, I; Ndengele, MM; Cuzzocrea, S; Reboucas, JS; Spasojevic, I 
2008 
Yes 
Free Radical Biology and Medicine
ISSN: 0891-5849
EISSN: 1873-4596 
45 
Suppl. 
S106-S106 
English 
WOS:000260867900301 
has other version or edition 551569 Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite-mediated pathways
is part of a larger document 3452652 SFRBM's 15th Annual Meeting: Program and Abstracts
Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, partly because reduced analgesic effectiveness with chronic opiate therapy (i.e., tolerance) leads to escalating doses and distressing side effects. We have recently reported that peroxynitrite (ONOO–) mediated nitroxidative stress in the dorsal horn of the spinal cord plays a critical role in the induction and development of antinociceptive tolerance to morphine. These results provide a valid pharmacological basis for developing ONOO– decomposition catalysts as potent adjuncts to opiates in the management of pain. Mn(III) cationic, ortho N-alkylpyridylporphyrins are the most potent ONOO– scavengers thus far reported. the ethyl and hexyl analogues, MnTE-2-PyP5+ and MnTnHex-2-PyP5+ decompose ONOO– with nearly identical rate constant of kcat >>107 M-1 s-1. Yet, MnTnHex-2-PyP5+ is significantly more lipophilic, and thus more bioavailable. Consequently, it is 30-fold more effective in reversing morphine tolerance than its ethyl analogue. While FeTM-4-PyP5+ is able to dismute superoxide and reduce ONOO– at similar rate constants as analogues and similarly hydrophilic MnTE-2-PyP5+ at pH 7.8, it is 10-fold less effective in reversing morphine tolerance; it is further 300-fold less effective than a lipophilic MnTnHex-2-PyP5+. Both Mn porphyrins decrease levels of TNF-, IL-1 and IL-6 to normal values. Neither of them affect acute morphine antinociceptive effect, nor do they cause motor function impairment. We have recently shown that anionic porphyrin, Mn(III) tetrakis(4-carboxylatophenyl)porphyrin, MnTBAP is selective in removing ONOO– over O2•–, yet at ~ 2 orders of magnitude lower efficacy than MnTE-2-PyP5+ and MnTnHex-2-PyP5+, which in turn parallels up to 100-fold lower ability to reverse morphine tolerance. Taken together these data (1) support the role of ONOO– rather than O2•– as a major mechanism in blocking the development of morphine tolerance, and (2) show that lipophilicity is a critical parameter in enhancing the potency of such novel ONOO– decomposition catalysts. DS and IBH acknowledge support from NIH R01 DA024074, IS from DUCCC Core grant 5-P30-CA14236-29, and IBH from NIAID grant 5-U19-AI067798-03. 
Society for Free Radical Biology and Medicine 15th Annual Meeting 
Indianapolis, IN 
November 19-23, 2008