Abstract
The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation, which can be reversed by the μ-opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, reemergence of MOR agonist–induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist methocinnamox (MCAM) antagonizes hypoventilation by the nonmorphinan fentanyl and the morphinan heroin in laboratory animals with an unusually long duration of action. Whole-body plethysmography was used to compare the potency and effectiveness of MCAM and naloxone for preventing and reversing hypoventilation by fentanyl, heroin, and the ultrapotent and longer-acting fentanyl analogs carfentanil and 3-methylfentanyl in male rats breathing normal air. Sessions comprised a 45-minute habituation period followed by intravenous administration of saline or an acute dose of MOR agonist. The rank order of potency to decrease ventilation was 3-methylfentanyl > carfentanil > fentanyl > heroin. MCAM (0.0001–0.1 mg/kg) and naloxone (0.0001–0.01 mg/kg) dose dependently reversed hypoventilation by 3-methylfentanyl (0.01 mg/kg), carfentanil (0.01 mg/kg), fentanyl (0.1 mg/kg), or heroin (3.2 mg/kg). For prevention studies, MCAM, naloxone, or vehicle was administered intravenously 22, 46, or 70 hours prior to a MOR agonist. When administered 22 hours earlier, MCAM (0.1–1.0 mg/kg) but not naloxone (1.0 mg/kg) prevented hypoventilation by each MOR agonist. This study demonstrates the effectiveness of MCAM at reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs that have a long duration of action.
SIGNIFICANCE STATEMENT The number of opioid overdose deaths increased over the past decade despite the availability of antagonists that can prevent and reverse the effects of opioids. This study demonstrates the effectiveness and long duration of action of the μ-opioid receptor (MOR) antagonist methocinnamox (MCAM) for reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs. These results provide support for the notion that MCAM has the potential to positively impact the ongoing opioid crisis by reversing and preventing opioid overdose.
Footnotes
- Received November 22, 2023.
- Accepted February 9, 2024.
This work was funded by National Institutes of Health National Institute on Drug Abuse [Grants UG3DA048387, UG3DA048387-S1, and R01DA048417] (to C.P.F.) and [Grant R01DA058018] (to T.H.) and by the Welch Foundation [Grant AQ-0039] (to C.P.F.). Funding sources were not involved beyond financial support of the present study. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institutes of Health or National Institute on Drug Abuse.
T.H. and N.P.H. have no conflicts to declare. C.P.F. is coholder of a US patent for methocinnamox.
Portions of these data were presented as follows:
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- Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics
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