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

Abstract

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 [V E ]) 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 V E . 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 respiratorydepressant effects of opioids, thereby improving treatment of opioid overdose.

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats

“…While these behavioral effects are predicted for a drug with the pharmacological properties of MCAM in vitro, these results also indicate that acute pain could be treated through mechanisms other than m-opioid receptors in patients taking MCAM for opioid abuse or overdose. These results extend those of previous studies on MCAM (Broadbear et al, 2000;Peckham et al, 2005;Gerak et al, 2019;Maguire et al, 2019) to other measures of m-opioid receptor agonism and to subjects physically dependent on morphine. Taken together, studies in mice, rats, and nonhuman primates provide compelling support for the potential use of MCAM for treating OUD as well as opioid overdose.…”

“…MCAM attenuated the acute effects of m-opioid receptor agonists in a dose-and time-related manner. Sustained antagonism by MCAM has been reported (Broadbear et al, 2000;Peckham et al, 2005;Gerak et al, 2019;Maguire et al, 2019); however, the current study extends previous findings in several ways. First, although MCAM was shown to attenuate the antinociceptive effects of morphine in rodents (Broadbear et al, 2000;Peckham et al, 2005), antagonism was monitored for only 2 days.…”

“…In contrast, the surmountable antagonism produced by naltrexone and naloxone is not selective. MCAM does not appear to have efficacy at any opioid receptor and, when given alone, does not produce antinociceptive effects or alter respiration, although it attenuates the reinforcing, antinociceptive, and respiratory-depressant effects of m-opioid receptor agonists in mice, rats, and nonhuman primates (Broadbear et al, 2000;Peckham et al, 2005;Gerak et al, 2019;Maguire et al, 2019). In the presence of MCAM, large doses of morphine can produce antinociceptive effects, although these effects might be mediated by other receptors (e.g., k-opioid receptors) (Takemori and Portoghese, 1987;Peckham et al, 2005) rather than reflect surmountability at m-opioid receptors.…”

“…In the presence of MCAM, large doses of morphine can produce antinociceptive effects, although these effects might be mediated by other receptors (e.g., k-opioid receptors) (Takemori and Portoghese, 1987;Peckham et al, 2005) rather than reflect surmountability at m-opioid receptors. Moreover, these antagonist effects are persistent, lasting for a week or more in monkeys (Gerak et al, 2019;Maguire et al, 2019). In nonhuman primates, doses of MCAM larger than those that attenuate the abuse-related and toxic effects of opioids do not attenuate self-administration of nonopioids (e.g., cocaine), decrease responding for food, or alter heart rate, blood pressure, body temperature, or activity (Maguire et al, 2019), suggesting that MCAM is safe and not likely to produce unexpected adverse effects.…”

Acute and chronic stress prevents responses to pain in zebrafish: evidence for stress-induced analgesia

“…Bosse and Peterson, 2017;Costa et al, 2019b); thus, future studies should explore the duration of action in fish. In mammals, naloxone has a short duration of action (∼15-30 min), requiring re-administration in cases of opioid overdose (Gerak et al, 2019). Naloxone is also known to affect behaviour in rodents, with mice being more anxious and displaying hyperalgesia (Bertolini et al, 1978;Grevert and Goldstein, 1977), although in the present study naloxone did not significantly affect swimming speed, fractal dimension or time spent at the bottom of the tank in NX-control zebrafish.…”