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Delta/mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression: assessment of therapeutic index in male Sprague Dawley rats

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Abstract

Rationale and objectives

Although delta/mu receptor interactions vary as a function of behavioral endpoint, there have been no assessments of these interactions using assays of pain-depressed responding. This is the first report of delta/mu interactions using an assay of pain-depressed behavior.

Methods

A mult-cycle FR10 operant schedule was utilized in the presence of (nociception) and in the absence of (rate suppression) a lactic acid inflammatory pain-like manipulation. SNC80 and methadone were used as selective/high efficacy delta and mu agonists, respectively. Both SNC80 and methadone alone produced a dose-dependent restoration of pain-depressed responding and dose-dependent response rate suppression. Three fixed ratio mixtures, based on the relative potencies of the drugs in the nociception assay, also produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that all three mixtures produced supra-additive antinociceptive effects and simply additive sedation effects.

Conclusions

The therapeutic index (TI) inversely varied as a function of amount of SNC80 in the mixture, such that lower amounts of SNC80 produced a higher TI, and larger amounts produced a lower TI. Compared to literature using standard pain-elicited assays, the orderly relationship between SNC80 and TI reported here may be a unique function of assessing pain-depressed behavior.

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Funding

This research was supported by an NIH COBRE grant (P20GM103643) that supports an animal behavior core facility and a National Institutes of Health (NIAMS) R15 AREA grant (AR054975-02A1) to G.W.S. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse.

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Authors and Affiliations

  1. Department of Psychology, University of New England, Biddeford, ME, 04005, USA

    Katherine Cone, Janell Lanpher, Abigail Kinens, Philomena Richard, Sarah Couture, Rebecca Brackin, Emily Payne, Kylee Harrington & Glenn W. Stevenson

  2. Drug Design and Synthesis Section, Molecular Targets and Medications Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, 20850, USA

    Kenner C. Rice

  3. Center for Excellence in the Neurosciences, University of New England, Biddeford, Maine, 04005, USA

    Glenn W. Stevenson

Authors
  1. Katherine Cone
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  2. Janell Lanpher
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  3. Abigail Kinens
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  4. Philomena Richard
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  5. Sarah Couture
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  6. Rebecca Brackin
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  7. Emily Payne
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  8. Kylee Harrington
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  9. Kenner C. Rice
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  10. Glenn W. Stevenson
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Corresponding author

Correspondence to Glenn W. Stevenson.

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All studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health, and procedures were approved by the University of New England Institutional Animal Care and Use Committee (IACUC).

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Cone, K., Lanpher, J., Kinens, A. et al. Delta/mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression: assessment of therapeutic index in male Sprague Dawley rats. Psychopharmacology 235, 1609–1618 (2018). https://doi.org/10.1007/s00213-018-4876-x

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  • DOI: https://doi.org/10.1007/s00213-018-4876-x

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