Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

The U.S. Department of Homeland Security (DHS) considers high potency opioids such as fentanyl to be a chemical threat because they can be delivered as an aerosol to cause a mass casualty event. Current evidence indicates that naloxone, the main rescue agent for an opioid overdose, may not be fully effective and that non-opioid receptor mechanisms may contribute to lethal respiratory depression. Thus, non-opioids respiratory stimulants may be useful as an adjunct to boost the effect of naloxone. The current proposal will determine the effectiveness of the α2 noradrenergic antagonist atipamezole to serve as a useful rescue adjunctive. Rats will be given a dose of fentanyl that produces profound motoric incapacitation and respiratory depression, followed by varying doses of atipamezole to determine to what extent, if any, atipamezole reverses the effect of fentanyl. Atipamezole will also be tested in combination with the long lasting opioid antagonist naltrexone to reverse the effects of fentanyl. In vitro cell-based assays will also be performed to determine if atipamezole functions at any of the known opioid receptor subtypes. If successful, results from this pilot application will be used as preliminary data to support an R01 application seeking to develop a novel chemical entity with potent α2-noradrenergic antagonist activity as a rescue adjunctive.