Opioid-Induced Tolerance and Dependence in Mice Is Modulated by the Distance between Pharmacophores in a Bivalent Ligand Series

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 52; pp. 19208 - 19213
• Main Authors: David J. Daniels, Natalie R. Lenard, Chris L. Etienne, Law, Ping-Yee, Sandra C. Roerig, Portoghese, Philip S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.12.2005; National Acad Sciences
• Subjects: Agonists; Analgesics - pharmacology; Analgesics, Opioid - pharmacology; Animals; Biological Sciences; Chemistry, Pharmaceutical - methods; Dose-Response Relationship, Drug; Drug interactions; Drug tolerance; Lactose tolerance test; Ligands; Male; Mice; Mice, Inbred ICR; Models, Chemical; Models, Statistical; Morphine; Morphine - pharmacology; Morphine dependence; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics; Narcotics - metabolism; Opioid analgesics; Opioid receptors; Pharmacology; Receptors; Receptors, Opioid, delta - chemistry; Receptors, Opioid, mu - chemistry; Rodents; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0506627102

Given the mounting evidence for involvement of δ opioid receptors in the tolerance and physical dependence of μ opioid receptor agonists, we have investigated the possible physical interaction between μ and δ opioid receptors by using bivalent ligands. Based on reports of suppression of antinociceptive tolerance by the δ antagonist naltrindole (NTI), bivalent ligands [$\mu -\delta$agonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from NTI and the μ agonist oxymorphone, have been synthesized and evaluated by intracerebroventricular (i.c.v.) administration in the tail-flick test in mice. In acute i.c.v. studies, the bivalent ligands functioned as agonists with potencies ranging from 1.6- to 45-fold greater than morphine. In contrast, the monovalent μ agonist analogues were substantially more potent than the MDAN congeners and were essentially equipotent with one another and oxymorphone. Pretreatment with NTI decreased the ED50values for MDAN-19 to a greater degree than for MDAN-16 but had no effect on MDAN-21. Chronic i.c.v. studies revealed that MDAN ligands whose spacer was 16 atoms or longer produced less dependence than either morphine or μ monovalent control MA-19. On the other hand, both physical dependence and tolerance were suppressed at MDAN spacer lengths of 19 atoms or greater. These data suggest that physical interaction between the μ and δ opioid receptors modulates$\mu -mediated$tolerance and dependence. Because MDAN-21 was found to be 50-fold more potent than morphine by the i.v. route (i.V.), it offers a previously uncharacterized approach for the development of analgesics devoid of tolerance and dependence.