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

ABSTRACT: Given the mounting evidence for involvement of delta opioid receptors in the tolerance and physical dependence of mu opioid receptor agonists, we have investigated the possible physical interaction between mu and delta opioid receptors by using bivalent ligands. Based on reports of suppression of antinociceptive tolerance by the delta antagonist naltrindole (NTI), bivalent ligands [mu-delta agonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from NTI and the mu 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 mu agonist analogues were substantially more potent than the MDAN congeners and were essentially equipotent with one another and oxymorphone. Pretreatment with NTI decreased the ED(50) 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 mu 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 mu and delta 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.

SUBMITTER: Daniels DJ

PROVIDER: S-EPMC1323165 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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

Daniels David J DJ Lenard Natalie R NR Etienne Chris L CL Law Ping-Yee PY Roerig Sandra C SC Portoghese Philip S PS

Proceedings of the National Academy of Sciences of the United States of America 20051219 52

Given the mounting evidence for involvement of delta opioid receptors in the tolerance and physical dependence of mu opioid receptor agonists, we have investigated the possible physical interaction between mu and delta opioid receptors by using bivalent ligands. Based on reports of suppression of antinociceptive tolerance by the delta antagonist naltrindole (NTI), bivalent ligands [mu-delta agonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from N ...[more]

PMID: 16365317

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Project description:BackgroundPain accompanies rheumatoid arthritis and other chronic inflammatory conditions and is difficult to manage. Although opioids provide potent analgesia, chronic opioid use can cause tolerance and addiction. Recent studies have demonstrated functional interactions between chemokine and opioid receptor signaling pathways. Reported heterodimerization of chemokine and opioid receptors led our group to develop bivalent compounds that bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is a novel bivalent compound containing a CCR5 antagonist and mu opioid receptor (MOR) agonist pharmacophores linked through a 22-atom spacer. We evaluated the efficacy of MCC22 in the K/B.g7 T-cell receptor transgenic mouse model of spontaneous inflammatory arthritis.MethodsMCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or nonarthritic control mice. Mechanical pain hypersensitivity was measured each day before and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to that of morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance.ResultsMCC22 provided ~ 3000-fold more potent analgesia than morphine in this model. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in nonarthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the antagonist pharmacophore.ConclusionsMCC22 is a novel bivalent ligand that targets CCR5 and MOR. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use.

Dataset Information

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

Publications

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

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