Methocinnamox Produces Sustained Antagonism of the Antinociceptive Effects of Morphine and Persistent Decreases in [3H]DAMGO Binding to μ Opioid Receptors in Rat Cortex

Abstract

The opioid crisis continues in the US despite the availability of pharmacotherapies that are effective in some patients. A novel μ opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action in blocking the effects of opioids, which could provide a substantial advantage over currently available medications, particularly for overdose. MCAM has been shown to attenuate the behavioral effects of μ, but not k, opioid receptor agonists, and this antagonism, which can last for several weeks, is thought to be due to pseudoirreversible binding of MCAM to μ opioid receptors. In the current study, a warm water tail withdrawal procedure was used to examine sustained antagonism by MCAM in one group of 8 rats. This study showed that 10 mg/kg MCAM attenuated the antinociceptive effects of morphine (1.78–17.8 mg/kg) 5 and 13 days after MCAM administration with antagonism beginning to wane 21 days after MCAM. In separate groups of 8 rats, that same dose of MCAM decreased [3H]DAMGO binding to μ opioid receptors in rat cortical homogenates measured 1, 5 and 21 days after MCAM injection, indicating that MCAM occupied μ opioid receptors at all time points tested. For example, maximal binding (Bmax) was 28.51 ± 3.33 and 30.96 ± 1.73 fmol/mg protein 5 and 21 days, respectively, after vehicle administration, and 16.03 ± 4.15 and 12.50 ± 1.27 fmol/mg protein 5 and 21 days, respectively, after administration of 10 mg/kg MCAM. Binding affinity (KD) was not markedly changed after MCAM administration. Thus, MCAM produces a sustained decrease in [3H]DAMGO binding to μ opioid receptors in rat cortex that parallels antagonism of the antinociceptive effects of μ opioid receptor agonists. This finding supports the notion that MCAM blocks the behavioral effects of μ opioid receptor agonists by binding pseudoirreversibly to these receptors. The unique binding profile of MCAM to μ opioid receptors could increase the usefulness of MCAM as a treatment for opioid abuse and overdose.Support or Funding InformationSupported by NIH (R01DA005018 and R01048417) and the Welch Foundation (AQ‐0039).