Sunday, May 18, 2025
5/18/2025
Delineation of microRNA regulatory pathways that support fentanyl-seeking behavior - 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.
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