Methocinnamox (MCAM) is an Effective Long‐Term Antagonist of Peripheral Mu, but not Kappa or Delta Opioid Receptors In Vivo

Abstract

The United States is currently in the midst of an opioid abuse epidemic; deaths from synthetic opioids like fentanyl and its derivatives are increasing. Currently naloxone (Narcan), a competitive mu opioid receptor antagonist is the only pharmacological treatment for opioid overdose; reversing both respiratory depression and profound sedation. However, naloxone has a relatively short duration of action and thus its effects are limited. A long lasting mu opioid receptor antagonist called MCAM has been shown to attenuate the antinociceptive effects of morphine in mice for more than 48 hours (Broadbear et al., J Pharmacol Exp Ther, 294:933–940, 2000) and due to this long duration of action, may make a better treatment for opioid overdose and perhaps for opioid abuse. Because MCAM reduces mu receptor function for a longer period relative to kappa or delta opioid receptors, we have begun to examine if pain relief from either kappa or delta receptor agonists will be active while mu receptors remain occupied by MCAM. Using the Hargreaves method for thermal heat nociception, we determined the effect of intraplantar (i.pl.) pretreatment of MCAM or vehicle on peripherally mediated reduction in PGE2‐evoked thermal allodynia by DAMGO (mu agonist), U50488 (kappa agonist) or DPDPE (delta agonist). Injection of DAMGO (20μg/50 μl i.pl.), U50488 (0.1μg/50μl i.pl.) or DPDPE (20μg/50 μl i.pl.) produced a significant reduction in PGE2‐evoked thermal allodynia. Pretreatment with MCAM 15 min prior to PGE2 injection at 10nM (0.25μg/50μl i.pl), 50nM (1.25μg/50μl i.pl) or 20nM (0.5μg/50μl i.pl), had no effect on PGE2‐induced thermal hypersensitivity; however, it significantly inhibited the antinociceptive response to DAMGO, U50488 and DPDPE. The DAMGO‐mediated antinociception remained blocked 24 and 48h after a single administration of MCAM. By contrast, when tested 24h after administration, MCAM had no effect on U50488‐ or DPDPE‐mediated antinociceptive responses. Thus, MCAM displayed long‐term antagonism at mu opioid receptors but only a short antagonist effect at either kappa or delta opioid receptors. These data suggest that MCAM's long duration of antagonist action is selective for mu opioid receptors and that peripherally restricted delta and kappa receptor agonists may be a viable option for pain relief.Support or Funding InformationThe Addiction Research, Treatment & Training (ARTT) Center of Excellence at UT Health San Antonio.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.