Inhibition of the development of morphine tolerance by a potent dual μ-/δ-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2008-10, Vol.90 (4), p.651-657
• Main Authors: JINSMAA, Yunden, MARCZAK, Ewa D, BALBONI, Gianfranco, SALVADORI, Severo, LAZARUS, Lawrence H
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; Area Under Curve; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Intraventricular; Injections, Subcutaneous; Ligands; Male; Medical sciences; Mice; Morphine - pharmacology; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Oligopeptides - pharmacology; Reaction Time - drug effects; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, mu - antagonists & inhibitors; Somatostatin - analogs & derivatives; Somatostatin - pharmacology
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2008.05.008

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.