Effects of Acute and Repeated Methocinnamox Treatment on Fentanyl Self‐administration in Rhesus Monkeys

Opioid abuse remains a serious public health challenge despite the availability of effective medications. Recent studies showed that the pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) attenuates the reinforcing and respiratory‐depressant effects of heroin in rhesus monkeys, suggesting it could be an effective treatment for opioid abuse and overdose. The current study extends this work by evaluating MCAM for its capacity to attenuate the reinforcing effects of the potent, high‐efficacy opioid fentanyl. Because successful treatment of opioid use disorder requires long‐term and, usually, repeated treatment, the current study also evaluated effects of repeated MCAM administration. Four rhesus monkeys responded for i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion) under a fixed‐ratio 30 schedule. Once responding was stable, naltrexone (0.0032, 0.01, or 0.032 mg/kg) or MCAM (0.1 or 0.32 mg/kg) was administered s.c. prior to a session. On a separate occasion, 0.32 mg/kg of MCAM was injected every 12 days for a total of 5 administrations over 49 days. Cocaine was substituted for fentanyl every fourth session to examine the selectivity of effects of MCAM. When given acutely, both doses of MCAM decreased responding for fentanyl on the day of treatment, with the larger dose (0.32 mg/kg) decreasing the number of infusions from an average of 24 under baseline to 7. Responding remained significantly lower than baseline for 2 and 14 days following administration of 0.1 and 0.32 mg/kg of MCAM, respectively. Naltrexone also decreased fentanyl self‐administration, with the largest dose (0.032 mg/kg) decreasing the number of infusions from 26 under baseline to 3 after treatment; however, responding returned to baseline the next day. When given every 12 days, MCAM decreased responding for fentanyl for more than 70 days; the time for responding to recover after 5 injections of MCAM was not different from the time to recovery after 1 injection. MCAM did not alter responding for cocaine in either experiment. MCAM decreased self‐administration of the potent, high‐efficacy opioid fentanyl but not cocaine. Effects of a single injection of MCAM lasted much longer (> 2 weeks) than those of naltrexone (< 24 hr), and MCAM remained effective for over 2 months with repeated treatment. These results confirm and extend previous studies, demonstrating that MCAM produces longlasting and selective suppression of opioid self‐administration and that MCAM remains effective following repeated administration. Moreover, recovery of responding following discontinuation of repeated MCAM treatment indicates that the opioid system was not disrupted. The long duration of action of MCAM is likely due, at least in part, to pseudoirreversible binding to mu opioid receptors, suggesting it would insurmountably block the abuse‐related effects of opioids. Taken together, these data indicate that MCAM could be a safe, effective, and long‐acting treatment for opioid use disorder and overdose. Support or Funding Information This work was supported, in part, by the National Institutes of Health [R01DA005018, R01DA048417, and R01DA007315] and the Welch Foundation [AQ‐0039].