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Synergistic antihyperalgesic and antinociceptive effects of morphine and methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024): a positive allosteric modulator at α2GABAA and α3GABAA receptors

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Abstract

Rationale

Opioid and GABAA receptors are both located in central nociceptive pathways, and compounds that activate these receptors have pain-relieving properties. To date, the interactive effects of concurrent administration of these compounds in preclinical models of pain-like behaviors have not been assessed.

Objective

The purpose of this study was to examine the interactive effects of the μ-opioid agonist morphine and the α2GABAA and α3GABAA receptor positive allosteric modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024) in preclinical models of mechanical hyperalgesia and thermal nociception.

Methods

The antihyperalgesic and antinociceptive effects of morphine and MP-III-024 administered alone were assessed initially, followed by fixed-ratio mixtures of MP-III-024/morphine combinations. Drug interaction data were analyzed using isobolographic and dose-addition analyses. All studies were conducted in male CD-1 mice.

Results

In the assay of mechanical hyperalgesia, each compound produced dose-dependent antihyperalgesic effects, whereas only morphine was effective on thermal nociception. Fixed-ratio mixtures of MP-III-024/morphine were also dose-dependently effective in both procedures. These drug combination studies revealed that morphine and MP-III-024 produced supra-additive (synergistic) effects in both assays, depending on their relative proportions.

Conclusions

These results demonstrate an interaction between α2GABAA and α3GABAA receptor- and μ-opioid receptor-mediated signals and suggest that combination therapy may be useful for the treatment of pain-related disorders.

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Acknowledgments

This work was supported by internal funds from Rowan University and Cooper Medical School of Rowan University. We also acknowledge the NIH for generous financial support (DA041560, DA043204, NS076517), the Milwaukee Institute for Drug Discovery and the University of Wisconsin-Milwaukee’s Shimadzu Laboratory for Advanced and Applied Analytical Chemistry for help with spectroscopy, and the National Science Foundation (Division of Chemistry, CHE-1625735).

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Authors and Affiliations

  1. Department of Chemistry & Biochemistry, Department of Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ, 08028, USA

    Mohammad A. Rahman & Thomas M. Keck

  2. Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA

    Michael M. Poe, Dishary Sharmin & James M. Cook

  3. Department of Biomedical Sciences Camden, Cooper Medical School of Rowan University, Camden, NJ, 08103, USA

    Bradford D. Fischer

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  1. Mohammad A. Rahman
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Correspondence to Bradford D. Fischer.

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Rahman, M.A., Keck, T.M., Poe, M.M. et al. Synergistic antihyperalgesic and antinociceptive effects of morphine and methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024): a positive allosteric modulator at α2GABAA and α3GABAA receptors. Psychopharmacology 238, 1585–1592 (2021). https://doi.org/10.1007/s00213-021-05791-1

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