ABSTRACT/SUMMARY This application for a supplement to parent grant UG3DA048387 is in response to Notice of Special Interest NOT-DA-21-032 “Administrative Supplements for research on fentanyl and derivatives.” The opioid crisis has worsened significantly during the COVID-19 pandemic, in part because of increasing availability of fentanyl and potent fentanyl analogs. Many overdoses involve more than one drug, often an opioid and a stimulant drug, although it is unclear whether stimulants alter the toxic effects of opioids and reversal of those effects by naloxone. The value of naloxone is limited by its short duration of action and that its antagonism can be surmounted by taking more agonist. After rescue from overdose, protection by naloxone often wanes before the effects of the opioid receptor agonist decrease, resulting in the reemergence of ventilatory depression possibly leading to death. Fatal ventilatory depression can occur in the presence of naloxone if an individual continues taking opioids, and there are reports of the need for larger doses and/or more frequent administration of naloxone to reverse and protect against overdose from fentanyl, compared with reversal of overdose from other opioids. Methocinnamox (MCAM) is a long-acting µ opioid receptor antagonist that reverses and prevents the ventilatory-depressant effects of fentanyl. It is not known whether MCAM is equally effective (potent) in reversing ventilatory depression by different opioids. Some studies suggest that opioid receptor antagonists, such as naloxone and naltrexone, do not block effects of different opioids equally and that mixtures of antagonists might be more effective than antagonists alone. Studies in this proposal will address the following: 1) investigate reversal of and protection from ventilatory depression by heroin and by fentanyl and related analogs; 2) compare the novel opioid receptor antagonist MCAM with naloxone and MCAM/naloxone mixtures; 3) characterize the ventilatory-depressant effects of heroin/methamphetamine and fentanyl/methamphetamine mixtures and reversal of those effects by naloxone and MCAM, alone and together; and 4) test for sex differences in the ventilatory-depressant effects of opioids and reversal of those effects by naloxone and MCAM, alone and together. Two specific aims will test the following hypotheses: 1) naloxone is less potent at reversing ventilatory depression by fentanyl and related analogs compared with reversal of ventilatory depression by heroin; 2) MCAM has similar potency at reversing ventilatory depression by all four opioids; 3) methamphetamine does not alter the ventilatory-depressant effects of fentanyl or heroin nor reversal of those effects by antagonists; 4) mixtures of MCAM and naloxone are more effective than either antagonist alone at reversing and protecting against ventilatory depression; and 5) there are no sex differences in the effects of drugs in this study. By characterizing reversal of ventilatory depression of different opioids alone and with methamphetamine, these studies will help guide the treatment of overdose, perhaps including novel opioid receptor antagonists like MCAM or mixtures of antagonists.

PROJECT NARRATIVE The opioid crisis has worsened significantly during the COVID-19 pandemic, fueled in part by increasing availability of fentanyl and related analogs that are easy to synthesize, inexpensive, potent, often marketed as other drugs, and reportedly more difficult to antagonize than opioids such as heroin. Proposed studies will assess the ability of naloxone and a novel, long-acting opioid receptor antagonist methocinnamox, alone and together, to rescue rats from the ventilatory-depressant effects of fentanyl-like drugs and heroin. Results of these studies will help guide clinicians in their efforts to rescue opioid overdose victims.