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. 2013 Jul 9;110(28):11595-9.
doi: 10.1073/pnas.1305461110. Epub 2013 Jun 24.

Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

Eyup Akgün  1 , Muhammad I Javed, Mary M Lunzer, Branden A Smeester, Al J Beitz, Philip S Portoghese
Affiliations

Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

Eyup Akgün et al. Proc Natl Acad Sci U S A. .

Abstract

The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ∼9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >10(6) therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.

Keywords: MPEP; respiratory depression; tolerance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Mu agonist, oxymorphone 1, and mGluR5 antagonist, M-MPEP2, as models for the pharmacophores in compounds 3, 4a–4d, 5, and 6.
Fig. 2.
Fig. 2.
Time-course of antinociception for MMG22 in mice pretreated with LPS.
See this image and copyright information in PMC

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References

    1. Guo Y, Wang HL, Xiang XH, Zhao Y. The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction. Neurosci Biobehav Rev. 2009;33(6):864–873. - PubMed
    1. Patel S, et al. Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]F-PEB. Nucl Med Biol. 2007;34(8):1009–1017. - PubMed
    1. Gasparini F, et al. [(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett. 2002;12(3):407–409. - PubMed
    1. Lee JS, Ro JY. Peripheral metabotropic glutamate receptor 5 mediates mechanical hypersensitivity in craniofacial muscle via protein kinase C dependent mechanisms. Neuroscience. 2007;146(1):375–383. - PubMed
    1. Aoki T, Narita M, Shibasaki M, Suzuki T. Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in mice. Eur J Neurosci. 2004;20(6):1633–1638. - PubMed

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