Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel μ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys.

One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [VE]) of heroin in five monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared with those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased VE MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve rightward at least 10-fold. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 minutes after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared with those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 minutes, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than opioid receptor antagonists currently in use. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose.

Gerak LR ，Maguire DR ，Woods JH ，Husbands SM ，Disney A ，France CP ... -  《-》

Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats.

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).

Jimenez VM Jr ，Castaneda G ，France CP 《-》

Effects of Daily Methocinnamox Treatment on Fentanyl Self-Administration in Rhesus Monkeys.

Methocinnamox (MCAM), a long-acting μ-opioid receptor antagonist, attenuates the positive reinforcing effects of opioids, such as heroin and fentanyl, suggesting it could be an effective treatment of opioid use disorder (OUD). Because treatment of OUD often involves repeated administration of a medication, this study evaluated effects of daily injections of a relatively small dose of MCAM on fentanyl self-administration and characterized the shift in the fentanyl dose-effect curve. Rhesus monkeys (3 males and 2 females) lever-pressed for intravenous infusions of fentanyl (0.032-10 μg/kg infusion) or cocaine (32-100 μg/kg infusion) under a fixed-ratio 30 schedule. MCAM (0.032 mg/kg) or naltrexone (0.0032-0.032 mg/kg) was administered subcutaneously 60 or 15 minutes, respectively, before sessions. When administered acutely, naltrexone and MCAM decreased fentanyl self-administration, with effects of naltrexone lasting less than 24 hours and effects of MCAM lasting for up to 3 days. Daily MCAM treatment attenuated responding for fentanyl, but not cocaine; effects were maintained for the duration of treatment with responding recovering quickly (within 2 days) following discontinuation of treatment. MCAM treatment shifted the fentanyl dose-effect curve in a parallel manner approximately 20-fold to the right. Naltrexone pretreatment decreased fentanyl intake with equal potency before and after MCAM treatment, confirming sensitivity of responding to antagonism by an opioid receptor antagonist. Although antagonist effects of treatment with a relatively small dose were surmountable, MCAM produced sustained and selective attenuation of opioid self-administration, supporting the view that it could be an effective treatment of OUD. SIGNIFICANCE STATEMENT: Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a long-acting μ-opioid receptor antagonist that blocks the reinforcing and ventilatory depressant effects of opioids in nonhuman subjects. This study demonstrates that daily treatment with MCAM reliably and selectively decreases fentanyl self-administration, further supporting the potential therapeutic utility of this novel antagonist.

Maguire DR ，France CP 《-》

Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys.

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n = 5) or cocaine (n = 4) under a fixed-ratio schedule. Another group (n = 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n = 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.

Maguire DR ，Gerak LR ，Woods JH ，Husbands SM ，Disney A ，France CP ... -  《-》

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

Minervini V ，Disney A ，Husbands SM ，France CP ... -  《-》