Long‐term Antagonism of Mu Opioid Receptors by Methocinnamox (MCAM) without Adverse Effects on Memory
Authors: Minervini Vanessa , France Charles 
Published: April 2020

Opioid abuse remains a serious public health problem. Methocinnamox (MCAM) is a mu opioid receptor antagonist that has pharmacological properties (e.g., pseudoirreversible binding to mu opioid receptors) that might make it especially well suited for treating opioid abuse and overdose. The endogenous opioid system is involved in cognition and motivation, and long‐term blockade of mu opioid receptors by MCAM might adversely impact complex operant behavior involving memory. This study characterized the effects of MCAM in five adult rhesus monkeys (n=1 male and n=4 females) responding for sucrose pellets under a delayed matching‐to‐sample task. Ten touches (sampling responses) on a colored rectangle (e.g., blue), displayed on a touch‐sensitive screen, presented two comparison stimuli, one of which matched the original stimulus (e.g., blue rectangle), either immediately or after a delay (1 – 32 sec). Touching the matching stimulus delivered a pellet and visual feedback followed by a 5‐sec inter‐trial interval, whereas touching the non‐matching stimulus terminated the trial and initiated a 35‐sec inter‐trial interval. Sessions comprised up to 100 trials in 90 min. Because MCAM was expected to have long‐term antagonist actions on muopioid receptors, the effects of the mu opioid receptor agonist morphine on delayed matching‐to‐sample accuracy and the number of trials completed were determined before and after MCAM administration to establish the duration of action of MCAM. Neither MCAM (0.32 mg/kg) nor morphine (1 – 5.6 mg/kg) impaired delayed matching‐to‐sample accuracy. Administered alone, morphine dose‐dependently decreased the number of trials completed to fewer than 20. When morphine was re‐tested 1 day after MCAM, monkeys completed all trials, and this single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days (and substantially longer in some subjects). Because morphine and MCAM were without effect on delayed matching‐to‐sample accuracy, the muscarinic receptor antagonist scopolamine (0.01 – 0.056 mg/kg) as well as the N‐methyl‐D‐aspartate antagonist phencyclidine (0.1 – 0.56 mg/kg) were studied to confirm sensitivity of the assay to memory‐impairing drug effects; each drug dose‐dependently decreased delayed matching‐to‐sample accuracy and the number of trials completed. MCAM did not impair memory (as measured by accuracy in a delayed‐matching‐sample task). This dose of MCAM attenuates i.v. self‐administration of mu opioid receptor agonists and reverses as well as protects against mu opioid receptor agonist‐induced respiratory depression, with the duration of these effects lasting approximately one week. These data are consistent with a favorable safety profile of MCAM, as MCAM provides long‐lasting antagonism of mu opioid receptors in the absence of any apparent adverse effects, making it a promising candidate for treating opioid abuse and overdose.Support or Funding InformationSupported by: National Institute on Drug Abuse grants R01DA005018 and R01DA048417.