RT Journal Article SR Electronic T1 Methocinnamox (MCAM) reverses and prevents fentanyl-induced ventilatory depression in rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP JPET-AR-2020-000387 DO 10.1124/jpet.120.000387 A1 Victor M Jimenez, Jr A1 Gabriel Castaneda A1 Charles P. France YR 2021 UL http://jpet.aspetjournals.org/content/early/2021/01/11/jpet.120.000387.abstract AB Opioid use disorder (OUD) affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. The FDA-approved opioid receptor antagonist naloxone (e.g. NarcanĀ®) 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 i.v. and s.c. 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 (VE) 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 i.v. and s.c. administration, respectfully. MCAM attenuated the antinociceptive effects of fentanyl, with antagonism lasting up to 5 days and more than 2 weeks after i.v. and s.c. 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, 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 s.c. and up to 5 days when administered i.v. These data suggest that MCAM might be particularly useful for rescuing individuals from opioid overdose, including fentanyl, as well as protecting against the reemergence of ventilatory depression (renarconization).