ABSTRACT
For the first time, over 100,000 deaths were caused by drug overdose in a 12-month period (April 2020 - April
2021) in the United States. Synthetic opioids, primarily fentanyl, accounted for over 60% of all overdose deaths
during this span (87% of opioid overdose deaths). Over the past decade, the number of overdose deaths
involving synthetic opioids has risen 20-fold, approaching 60,000 in 2020. The emergence of fentanyl analogs,
some of which are much more potent than fentanyl (e.g., carfentanil, reported to be ~100 times more potent than
fentanyl), pose serious risk to public health. Another dangerous characteristic of exposure to these drugs is that
they are predominantly taken unknowingly which, combined with their potency, increases the risk of overdose.
The opioid receptor antagonist naloxone is the only FDA-approved treatment for opioid overdose. While
naloxone has saved countless lives, its effectiveness is limited by its short duration of action and that its
antagonism is competitive – that is, that the effects of naloxone can be surmounted by taking more of an opioid
agonist. Clinical reports suggest that larger or more frequent doses of naloxone are required to reverse opioid
overdose involving carfentanil or other fentanyl analogs, and preclinical studies show reduced effectiveness of
opioid antagonists to antagonize the effects of carfentanil relative to other opioid agonists. The novel opioid
receptor antagonist methocinnamox (MCAM) binds non-competitively at the mu opioid receptor and has
extremely long-lasting effects. A recent study demonstrated that some effects of MCAM are mediated through
binding an allosteric site on the mu opioid receptor. This finding warrants further study and provides rationale for
evaluating the potential of using mixtures of antagonists to reverse opioid-induced ventilatory depression. The
proposed studies use whole-body plethysmography in rats to address current trends in opioid overdose death
and the need for development of new treatment options for opioid overdose, testing the hypotheses that the
effects of mixtures of opioid agonists will be greater than each drug when given alone, and that mixtures of the
opioid antagonists naloxone and MCAM will be more potent than naloxone alone at reversing the effects of opioid
agonists on ventilation. Aim 1 will determine the nature of the interaction between the effects of heroin, fentanyl,
and carfentanil on ventilation. Aim 2 will determine the nature of the interactions between naloxone, MCAM, and
diprenorphine for reversing the ventilatory depressive effects of heroin, fentanyl, and carfentanil, and begin to
assess the mechanism of this interaction. The proposed studies will determine the nature of interactions between
opioid agonists commonly involved in opioid overdose and evaluate whether mixtures of opioid antagonists might
be more effective alternatives to naloxone for reversing opioid overdose. Results from these studies will provide
valuable information related to recent trends in opioid overdose death and possible improvements in the
treatment of opioid overdose. The proposed training plan will develop my skills at designing, conducting, and
disseminating my independent research, paving the way to becoming a successful independent investigator.