Abstract:
With increased use of fentanyl or fentanyl-analog compounds in the United States, the opioid epidemic has
evolved into a `fentanyl epidemic.' Overdose deaths involving these extremely potent mu-opioid receptor
(MOR) agonists have increased ~30-40-fold in the last 20 years. Moreover, in 2021, drug overdose deaths in
the United States topped 100,000 for the first time ever and more than half of all deaths involved fentanyl or
fentanyl analogs. Yet, the brain neuroadaptations induced by fentanyl and fentanyl analog exposure remain
poorly described. Additionally, it is not known if the high amount of fentanyl-associated deaths are due to
fentanyl being `more addictive' than other opioids, or if fentanyl induces a unique set of neuroadaptations
associated with increased opioid seeking. The limited literature describing molecular alterations following
fentanyl exposure in comparison with other well-studied opioids such as morphine indicates divergency
amongst MOR agonists for neuroadaptations involving microRNA (miRNA) regulation and gene expression.
miRNAs inhibit protein translation to modulate gene expression and have recently emerged as critical
regulators of drug seeking for many drug classes. miRNAs have additional utility as biomarkers because
miRNAs are present in exosomes found in serum of peripheral blood samples. Investigation into the
relationship between drug exposure and regulation of brain miRNAs that can also be detected in the periphery
can be accomplished easily with rodent models of self-administration but has yet to be done. In this exploratory
project, we will use rat opioid self-administration to: 1) examine the acute and long-lasting effects of fentanyl or
the ultra-potent analog furanylfentanyl on exosomal blood serum and orbitofrontal cortex (OFC) brain
microRNA (miRNA) profiles; 2) compare the fentanyl-induced miRNA profiles to the less potent opioid heroin;
3) correlate fentanyl-induced blood and brain miRNA profiles to opioid seeking behavior at multiple timepoints;
and 4) directly compare fentanyl-, furanylfentanyl- and heroin-induced drug seeking behavior at response-
equivalent dosages to identify agonist-specific differences in long-lasting drug seeking behavior. This project
will provide critical insight into both the immediate and long-lasting molecular consequences of fentanyl and
furanylfentanyl exposure on brain neurochemistry and identify miRNA-mediated pathways associated with
opioid seeking. Therefore, this study provides an essential opportunity to understand the relationship between
blood and brain miRNA expression as an indication of opioid craving. Studies of blood miRNA profiles
associated with drug seeking behavior have translational potential, as biomarkers indicative of recovery from
substance use or relapse may help to inform patient care or treatment responsiveness.