Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

David J. Daniels, Natalie R. Lenard, Chris L. Etienne, Ping Yee Law, Sandra C. Roerig, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

228 Scopus citations


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 [μ-δ agonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from NTI and the μ agonist oxytnorphone, 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 ED50 values 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 μ-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.

Original languageEnglish (US)
Pages (from-to)19208-19213
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 27 2005


  • Antinociception
  • Heterodimers

ASJC Scopus subject areas

  • General


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