DOI
https://doi.org/10.25772/DM98-W683
Author ORCID Identifier
0000-0002-1695-6723
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
D. Matthew Walentiny, Ph.D.
Second Advisor
Patrick M. Beardsley, Ph.D.
Abstract
Opioid overdose and associated deaths involving opioid-induced respiratory depression (OIRD) began to accelerate beginning in 2015 with the emergence of illicitly manufactured fentanyl and its analogs and currently represents one of the most significant public health challenges in the United States. The increases in overdose deaths have occurred despite the increased availability of the opioid overdose reversal agent, naloxone, to first responders and the public. This new phase of the opioid epidemic has been paralleled by substantial growth in the co-use of opioids with stimulants, particularly methamphetamine. The objective of this dissertation is to ascertain whether fentanyl is particularly resistant to reversal by naloxone, characterize the potential respiratory toxicity of fentanyl-methamphetamine co-use, and evaluate the activity of non-opioid respiratory stimulants (analeptics) to determine their potential utility as adjunct reversal agents. To accomplish this, the respiratory depressant effects of fentanyl and oxycodone, their reversal by naloxone, and the modulation of basal and opioid-depressed respiration by psychostimulants, methylxanthines, and monoamine agonists were characterized using a specially designed three-phase whole-body plethysmography protocol to record breath frequency, tidal volume, and minute volume in awake and freely-moving male Swiss-Webster mice.
The findings of the present dissertation studies show that fentanyl is not uniquely resistant to reversal by naloxone relative to oxycodone when determined at equi-depressant doses under the present testing conditions and provides evidence that challenges the importance of non-opioid mechanisms in fentanyl’s respiratory depressant effects. Subsequent studies conducted with amphetamine-type psychostimulants administered alone and in combination with fentanyl provide the first evidence of their bidirectional effects on respiration. These results demonstrate the potential of fentanyl and methamphetamine co-administration to either exacerbate or mitigate respiratory toxicity, both of which have important implications for public health. Subsequent experiments with methamphetamine’s enantiomers and selective monoamine agonists provide evidence to support the differential contributions of monoamine receptors to the bidirectional respiratory effects of methamphetamine. Altogether, this body of work suggests hope and provides direction for the use of non-opioid analeptics to help combat the rise of overdose deaths and addresses a critical knowledge gap surrounding the respiratory consequences of fentanyl-methamphetamine co-use and its associated mechanisms.
Rights
© Harrison J Elder, Ph.D.
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2023