Abstract
Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics, Opioid / pharmacology*
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Animals
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Area Under Curve
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Dose-Response Relationship, Drug
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Drug Tolerance
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Injections, Intraventricular
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Injections, Subcutaneous
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Ligands
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Male
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Mice
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Morphine / pharmacology*
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Naltrexone / analogs & derivatives
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Naltrexone / pharmacology
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Narcotic Antagonists / pharmacology
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Oligopeptides / pharmacology*
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Reaction Time / drug effects
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Receptors, Opioid, delta / antagonists & inhibitors*
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Receptors, Opioid, mu / antagonists & inhibitors*
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Somatostatin / analogs & derivatives
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Somatostatin / pharmacology
Substances
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Analgesics, Opioid
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H-Dmt-Tic-Lys(Z)-NH-CH2-Ph
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Ligands
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Narcotic Antagonists
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Oligopeptides
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Receptors, Opioid, delta
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Receptors, Opioid, mu
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phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
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deltorphin I, Ala(2)-
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Somatostatin
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Naltrexone
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Morphine
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naltrindole