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HERO ID
551569
Reference Type
Journal Article
Title
Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite-mediated pathways
Author(s)
Batinic-Haberle, I; Ndengele, MM; Cuzzocrea, S; Reboucas, JS; Spasojevic, I; Salvemini, D
Year
2009
Is Peer Reviewed?
Yes
Journal
Free Radical Biology and Medicine
ISSN:
0891-5849
EISSN:
1873-4596
Volume
46
Issue
2
Page Numbers
212-219
Language
English
PMID
18983908
DOI
10.1016/j.freeradbiomed.2008.09.037
Web of Science Id
WOS:000262491000012
Relationship(s)
has other version or edition
975897
Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite mediated pathways
Abstract
Severe pain syndromes reduce the quality of life of 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. Peroxynitrite-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. This provides a valid pharmacological basis for developing peroxynitrite scavengers as potent adjuncts to opiates in the management of pain. The cationic Mn(III) ortho-N-alkylpyridylporphyrins MnTE-2-PyP5+ and MnTnHex-2-PyP5+ are among the most potent peroxynitrite scavengers, with nearly identical scavenging rate constants (~107 M- 1 s- 1). Yet, MnTnHex-2-PyP5+ is significantly more lipophilic and more bioavailable and, in turn, was 30-fold more effective in blocking the development of morphine antinociceptive tolerance than MnTE-2-PyP5+ using the hot-plate test in a well-characterized murine model. The hydrophilic MnTE-2-PyP5+ and the lipophilic MnTnHex-2-PyP5+ were 10- and 300-fold, respectively, more effective in inhibiting morphine tolerance than the hydrophilic Fe(III) porphyrin FeTM-4-PyP5+. Both Mn porphyrins decreased levels of TNF-[alpha], IL-1[beta], and IL-6 to normal values. Neither of them affected acute morphine antinociceptive effects nor caused motor function impairment. Also neither was able to reverse already established morphine tolerance. We have recently shown that the anionic porphyrin Mn(III) tetrakis(4-carboxylatophenyl)porphyrin is selective in removing ONOO- over O2-, but 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. These data (1) support the role of peroxynitrite rather than superoxide 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 peroxynitrite scavengers.
Keywords
Pain management; Morphine tolerance; Peroxynitrite; Nitrotyrosine; Mn porphyrins; MnTBAP; MnTE-2-PyP; MnTnHex-2-PyP; Peroxynitrite scavengers; Cytokines; Free radicals; SOD mimics
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