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Research ArticleBehavioral Pharmacology

Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats

Victor M. Jimenez Jr., Gabriel Castaneda and Charles P. France
Journal of Pharmacology and Experimental Therapeutics April 2021, 377 (1) 29-38; DOI: https://doi.org/10.1124/jpet.120.000387
Victor M. Jimenez Jr.
Departments of Pharmacology (V.M.J., G.C., C.P.F.), Psychiatry (C.P.F.), and Addiction Research, Treatment and Training Center of Excellence (V.M.J., G.C., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Gabriel Castaneda
Departments of Pharmacology (V.M.J., G.C., C.P.F.), Psychiatry (C.P.F.), and Addiction Research, Treatment and Training Center of Excellence (V.M.J., G.C., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Charles P. France
Departments of Pharmacology (V.M.J., G.C., C.P.F.), Psychiatry (C.P.F.), and Addiction Research, Treatment and Training Center of Excellence (V.M.J., G.C., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Abstract

Opioid use disorder affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. The Food and Drug Administration–approved opioid receptor antagonist naloxone (e.g., Narcan) is used currently to treat overdose; however, a short duration of action limits its clinical utility. Methocinnamox (MCAM) is a long-lasting opioid receptor antagonist that may reverse and prevent the ventilatory-depressant effects of fentanyl. This study compared the ability of naloxone (0.0001–10 mg/kg) and MCAM (0.0001–10 mg/kg) to reverse and prevent ventilatory depression by fentanyl and compared the duration of action of MCAM intravenously and subcutaneously in two procedures: ventilation and warm-water tail withdrawal. In male Sprague-Dawley rats (N = 8), fentanyl (0.0032–0.178 mg/kg, i.v.) decreased minute volume in a dose- and time-dependent manner with a dose of 0.178 mg/kg decreasing VE to less than 40% of control. MCAM and naloxone reversed the ventilatory-depressant effects of 0.178 mg/kg fentanyl in a dose-related manner. The day after antagonist administration, MCAM but not naloxone attenuated the ventilatory-depressant effects of fentanyl. The duration of action of MCAM lasted up to 3 days and at least 2 weeks after intravenous and subcutaneous administration, respectively. MCAM attenuated the antinociceptive effects of fentanyl, with antagonism lasting up to 5 days and more than 2 weeks after intravenous and subcutaneous administration, respectively. Reversal and prolonged antagonism by MCAM might provide an effective treatment option for the opioid crisis, particularly toxicity from fentanyl and related highly potent analogs.

SIGNIFICANCE STATEMENT This study demonstrates that like naloxone, methocinnamox (MCAM) reverses the ventilatory-depressant effects of fentanyl in a time- and dose-related manner. However, unlike naloxone, the duration of action of MCAM was greater than 2 weeks when administered subcutaneously and up to 5 days when administered intravenously. These data suggest that MCAM might be particularly useful for rescuing individuals from opioid overdose, including fentanyl overdose, as well as protecting against the reemergence of ventilatory depression (renarconization).

Footnotes

    • Received October 19, 2020.
    • Accepted January 6, 2021.
  • This work was supported by National Institutes of Health National Institute on Drug Abuse [Grants R01-DA05018 and R01-DA048417] (to C.P.F.), the Welch Foundation [Grant AQ-0039] (to C.P.F.), and T32 Training Program [Grant T32DA031115] (to C.P.F.). All funding sources had no involvement beyond financial support of this study. The content is solely the responsibility of the authors and does not represent the official views of National Institutes of Health or National Institute on Drug Abuse.

  • https://doi.org/10.1124/jpet.120.000387.

  • Disclosure/Conflict of Interest: C.P.F. is coholder of a provisional US patent for MCAM

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 1
1 Apr 2021
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Research ArticleBehavioral Pharmacology

MCAM Reverses and Prevents Fentanyl Ventilatory Depression

Victor M. Jimenez, Gabriel Castaneda and Charles P. France
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 29-38; DOI: https://doi.org/10.1124/jpet.120.000387

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Research ArticleBehavioral Pharmacology

MCAM Reverses and Prevents Fentanyl Ventilatory Depression

Victor M. Jimenez, Gabriel Castaneda and Charles P. France
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 29-38; DOI: https://doi.org/10.1124/jpet.120.000387
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