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
HERO ID
975897
Reference Type
Journal Article
Subtype
Abstract
Year
2008
Language
English
| HERO ID | 975897 |
|---|---|
| Material Type | Abstract |
| In Press | No |
| Year | 2008 |
| Title | Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite mediated pathways |
| Authors | Salvemini, D; Batinic-Haberle, I; Ndengele, MM; Cuzzocrea, S; Reboucas, JS; Spasojevic, I |
| Journal | Free Radical Biology and Medicine |
| Volume | 45 |
| Issue | Suppl. |
| Page Numbers | S106-S106 |
| Abstract | 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. |
| Wosid | WOS:000260867900301 |
| Url | http://www.sciencedirect.com/science/article/pii/S0891584908006278 |
| Is Certified Translation | No |
| Dupe Override | No |
| Conference Location | Indianapolis, IN |
| Conference Name | Society for Free Radical Biology and Medicine 15th Annual Meeting |
| Conference Date | November 19-23, 2008 |
| Is Public | Yes |
| Language Text | English |
| Relationship(s) |