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Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys

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Abstract

Rationale

Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory.

Objective

This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption.

Results

Neither MCAM (0.32 mg/kg) nor morphine (1–5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01–0.056 mg/kg) and phencyclidine (0.1–0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed.

Conclusions

MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.

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Acknowledgments

The authors thank Lisa Gerak and David Maguire for the helpful comments on the manuscript.

Funding

This work was supported by the National Institutes of Health (NIH) National Institute on Drug Abuse (Grants R01DA005018 (to CPF), R01DA048417 (to CPF), and R01DA07315 (to SMH)) and the Welch Foundation (Grant AQ-0039 (to CPF)). The content expressed here is solely the responsibly of the authors and does not necessarily represent the views of the NIH.

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Authors and Affiliations

  1. Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive (Mail Code 7764), San Antonio, TX, 78229, USA

    Vanessa Minervini & Charles P. France

  2. Addiction Research, Treatment and Training (ARTT) Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Vanessa Minervini & Charles P. France

  3. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

    Alex Disney & Stephen M. Husbands

  4. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Charles P. France

Authors
  1. Vanessa Minervini
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  2. Alex Disney
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  3. Stephen M. Husbands
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  4. Charles P. France
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Corresponding author

Correspondence to Charles P. France.

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Conflict of interest

CPF is a coholder of a US provisional patent for MCAM.

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Minervini, V., Disney, A., Husbands, S.M. et al. Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys. Psychopharmacology 237, 3057–3065 (2020). https://doi.org/10.1007/s00213-020-05592-y

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  • DOI: https://doi.org/10.1007/s00213-020-05592-y

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