Methocinnamox: Sustained Antagonism of the Antinociceptive Effects of Morphine and Not Spiradoline in Rats

Abstract

The opioid epidemic continues in the US. Currently available pharmacotherapies for opioid abuse and overdose include mu opioid receptor agonists (methadone and buprenorphine) and antagonists (naltrexone and naloxone), and while each treatment can be effective, they have limitations. A novel mu opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action in blocking the abuse‐related and toxic effects of opioids, and its antagonist effects are not surmounted by subsequent administration of mu opioid receptor agonists. Consequently, MCAM might overcome the limitations of other antagonists, although other problems could emerge with long‐term blockade of mu opioid receptors (e.g. prescription opioids would be ineffective for treating pain). The current study measured antinociception using a warm water tail withdrawal procedure in rats and examined the persistence, surmountability, and selectivity of antagonism by MCAM. In 1 group of 8 rats, morphine dose‐effect curves were determined 1 day after MCAM administration and periodically thereafter, and in a different group of 8 rats, a dose‐effect curve for the kappa opioid receptor agonist spiradoline was determined 1 day after MCAM administration with morphine dose‐effect curves determined periodically thereafter. Morphine (1.78–17.8 mg/kg) and spiradoline (1–10 mg/kg) dose‐dependently increased the latency for rats to remove their tails from water maintained at 50°C. MCAM (1–10 mg/kg) attenuated the antinociceptive effects of morphine in a dose‐ and time‐dependent manner, with 10 mg/kg MCAM producing a 30‐fold rightward shift in the morphine dose‐effect curve 1 day after it was administered. For at least 37 days after administration of the largest dose of MCAM, doses of 178–560 mg/kg of morphine were needed to produce a maximal antinociceptive effect. In contrast, the spiradoline dose‐effect curve was not changed 1 day after administration of 10 mg/kg MCAM, although in the same rats the antinociceptive effects of morphine were attenuated 4 days later (i.e. 5 days after MCAM administration). Thus, MCAM produces a sustained and selective antagonism of the antinociceptive effects of mu opioid receptor agonists. Under these conditions, antagonism by MCAM was surmounted by very large doses of morphine, although it remains to be determined whether the antinociceptive effects of those doses of morphine are mediated by mu opioid receptors. Nevertheless, the selectivity of MCAM in antagonizing the effects of mu opioid receptor agonists suggests that pain could be treated through mechanisms other than mu opioid receptors in patients that are taking MCAM for opioid abuse or overdose.Support or Funding InformationSupported by NIH (R01DA005018; R01DA07315) and the Welch Foundation (AQ‐0039).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.