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.