Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys

Abstract

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

Fig. 1. Time- and dose-dependent effects of naltrexone on fentanyl self-administration.

a Time course of effects of naltrexone on fentanyl self-administration (n = 4). The number of fentanyl infusions per session is plotted across three consecutive sessions: immediately preceding a test (“Baseline”), 15 min after an injection of naltrexone (“Treatment”), and 1 day after an injection of naltrexone (“1 day after”). Each symbol indicates a test with a different dose of naltrexone. The shaded region shows the range across baseline sessions for individual monkeys, and the arrow and vertical dashed line indicate the day on which naltrexone was administered. b Naltrexone dose–effect curves plotted for each of three determinations during the course of the study (n = 4, except as indicated below). The mean number of fentanyl infusions is plotted for pretreatment with saline (above S) and increasing doses of naltrexone. All monkeys were tested with 0.0032, 0.01, and 0.032 mg/kg for the first determination. The range of doses tested varied across monkeys for the second and third determinations depending on effects of naltrexone, as follows: second determination, 0.001 mg/kg (n = 1) and 0.032 mg/kg (n = 2); third determination, 0.001 mg/kg (n = 1) and 0.032 mg/kg (n = 1). For both panels, symbols represent the mean (±1 SEM); filled symbols indicate data that are significantly different from baseline (a) or saline (b) according to a Dunnett’s test (p < 0.05).

Fig. 2. Effects of acute or repeated treatment with MCAM on self-administration of fentanyl or cocaine.

Panels a and b show effects of a single injection of 0.1 and 0.32 mg/kg MCAM, respectively; panel c shows effects of repeated injections of 0.32 mg/kg MCAM, with injections separated by 12 days. For all panels, n = 4 except for cocaine data in panel a which is n = 3 (see “Effects of acute MCAM administration” for more information). The number of infusions is plotted across consecutive days; symbols above “B” indicate data from the sessions preceding MCAM injection, whereas symbols above “T” indicate data from the session on the day of treatment (i.e., 60 min after MCAM injection) for panels a and b or the first MCAM injection in panel c. Symbols represent the mean (±1 SEM); filled symbols indicate data that are significantly different from baseline according to a Dunnett’s test (p < 0.05). The shaded region shows the range of the baseline sessions across individual monkeys, and the arrows and vertical dashed lines indicate the days on which MCAM was administered.

Fig. 3. Plasma concentration of MCAM following acute MCAM administration.

Plasma MCAM concentration in ng/ml is plotted as a function of time since MCAM administration. Symbols show data from indivdiual monkeys. The table inset shows pharmacokinetic parameters derived for each monkey. T_max is the observed time to reach the maximum concentration; C_max is the maximum concentration observed in plasma; and T_1/2 is an estimate of the time needed to reduce plasma levels of MCAM to half of the maximum. One monkey was excluded from the 360 min time point and another from the 2880 min time point because samples were not available for analysis.

Fig. 4. Plasma concentration of MCAM following repeated MCAM administration.

Plasma was collected immediately following the self-administration session on the day in which MCAM was given and on each of the following two days. Each triad of data points shows plasma MCAM concentration in ng/ml for an MCAM injection. Numbers along the abscissa indicate days since the first MCAM injection of the test; the data point above “C” indicates concentration in plasma collected before the experiment and prior to the first MCAM administration. Each data point represents the mean (±1 SEM) for four monkeys, except for day 25, when blood was not collected from one monkey, and for day 36, when an outlier was excluded (see “Results” for details). Filled symbols indicate means that are statistically different from baseline (data point above “C”) according to a Dunnett’s test (p < 0.05).