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

Abstract

Rationale-Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory.Objective-This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine as well as the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption.Results-Neither MCAM (0.32 mg/kg) nor morphine (1 -5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01 -0.056 mg/kg) and phencyclidine (0.1 -0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed.Conclusions-MCAM did not impair memory (as measured by accuracy in a delayedmatching-sample task) and did not decrease responding for or consumption of sucrose pellets.

Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats

“…MCAM is an opioid receptor antagonist with a long duration of action (Broadbear et al 2000;Gerak et al 2019a,b;Maguire et al 2019Maguire et al , 2020Minervini et al 2020;Peckham et al 2005). MCAM has been shown to antagonize several different effects of mu opioid receptor agonists in mice, rats, and nonhuman primates, including the ventilatory depressant effects of heroin in nonhuman primates.…”

Potential of Methocinnamox to Treat Opioid Misuse

“…48,98,102,103 The preclinical phase of MCAM drug development began in 2005 with testing in mice, rats, and non-human primates. 21,48,[95][96][97][98][99][100][101] Researchers aim to begin phase I clinical trials by 2022. 92 MCAM has the potential to transform the future of OUD treatment, thereby reducing the healthcare and societal burden caused by the opioid epidemic, 1,2 and improving the lives of millions.…”

“…22 Some studies have shown no statistically significant adverse effects nor potential ADRs with benzodiazepines and alcohol. 19,22,97 MCAM has not been shown to cause a decrease in response to food or alter heart rate, blood pressure, body temperature, or social and physical activity and no indication of developing tolerance nor physical dependence. 19,22 MCAM is currently the most potent and selective MOR antagonist and shows no agonistic effects, even at high concentrations, with the longest duration and highest potency when injected subcutaneously over other methods of administration.…”

“…19,22,98 MCAM also blocks the physiological and behavioral effects of MOR agonists such as unfavorable impacts of sensitivity to mechanical stimulation, gastrointestinal motility, appetite, and memory and other cognition, suggesting the adverse effect profile is encouraging. 21,22,25,97,101 However, it is important to recognize that no testing has been conducted in humans. 92 It is currently unknown if long-term blockade of the mu receptor would attenuate endorphin and enkephalin signaling sufficiently to reduce mood.…”

Countermeasures for Preventing and Treating Opioid Overdose

“…18 MCAM does not affect performance in monkeys responding under a delayed matching-to-sample (memory) task at doses that antagonize the response-rate decreasing effects of morphine in the same monkeys for a week or longer. 20 In vitro studies conducted under a NIDA contract (unpublished) found no effect of MCAM in the AMES (mutagenicity) assay or a bacterial cytotoxicity assay, no effect in the hERG (cardiac toxicity) assay, no effect on any of 6 isozymes in a cytochrome p450 inhibition assay, and, with the exception of opioid receptors, no significant affinity for 66 different receptors and enzymes, up to a concentration of 100 nM.…”