Investigating the role of locus coeruleus MU opioid receptors in fentanyl drug seeking

The National Institute on Drug Abuse awarded The Washington University $116,865 on August 3, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to investigate the role of locus coeruleus mu opioid receptors in fentanyl drug seeking.

The research establishes the specific contribution of the locus coeruleus, a brain region dense with mu opioid receptors, in modulating fentanyl-seeking behavior. Preliminary data from the investigator demonstrates that conditional knockout of mu opioid receptors on noradrenergic cells potentiates morphine place preference and increases fentanyl consumption in a two-bottle choice paradigm; this project aims to determine whether the locus coeruleus specifically drives those outcomes, distinguishing its role from broader noradrenergic system activity distributed across multiple brain regions and peripheral sites.

The award supports a project period through February 28, 2029, with work performed in St. Louis, Missouri. Washington University's Office of Sponsored Research Services serves as the recipient organization.

Abstract

Opioid addiction results in the death of tens of thousands of individuals in the U.S. Every year. That number is only continuing to grow. A large reason for the growing number of opioid-related deaths is the introduction and mass production of synthetic opioids like fentanyl. Synthetic opioids are much more potent than traditional opioids, and therefore their usage is more often associated with addiction and subsequent death. To combat this growing opioid epidemic, we need a better understanding of the brain regions that propagate opioid and, in particular, synthetic opioid, seeking. One potential critical modulator of opioid seeking is the locus coeruleus (LC). The LC, which is the origin of the primary central noradrenergic (NE) system, is a critical modulator of the somatic symptoms of opioid withdrawal and opioid reinstatement. Additionally, the LC densely express MU opioid receptors (MOR), the target receptor for synthetic opioids. However, despite its dense expression of MOR and its established role in opioid-related behaviors, the LC's role in opioid seeking is not well established. This proposal aims to establish the role of the LC and, in particular, LC MOR in fentanyl drug seeking. My preliminary data shows that a conditional knockout of MOR on noradrenergic cells potentiates morphine place preference and increases fentanyl consumption in a two-bottle choice paradigm. This data does not, however, implicate a specific brain region in the modulation of these behaviors. The NE system is a vast collection of ascending and descending projections across the brain, and dopamine beta hydroxylase, the rate limiting enzyme in the synthesis of norepinephrine, is also expressed in any epinephrine producing cells, as well as within the sympathetic ganglia, and adrenal glands. We therefore hypothesize that the LC is the region responsible for these findings, and a decrease in LC MOR will also increase fentanyl consumption. In aim 1 i will determine what chronic fentanyl exposure does to LC MOR; specifically, whether chronic fentanyl exposure downregulates LC MOR. To do so i will implant mice with osmotic minipumps for reliable and consistent delivery of fentanyl over a two-week period. Following this period, brain slices containing the LC will be collected and LC MOR will be assessed both functionally, with the use of whole-cell electrophysiological recordings, and physically, with the use of quantitative polymerase chain reaction. In aim 2 i will determine whether knockout of LC MOR drives fentanyl consumption. To do so i will first virally knockout LC MOR, after which mice will undergo a two-bottle choice paradigm of fentanyl consumption. I will then test whether our preliminary findings showing that a conditional knockout of NE MOR increases fentanyl consumption are being driven by the LC. Specifically, i will rescue LC MOR expression in these NE MOR conditional knockout mice before they undergo the same two- bottle choice fentanyl consumption paradigm. Overall, this proposal will help establish the role of the LC, and LC MOR specifically, in fentanyl consumption. Furthermore, IT will support my growth as an independent scientist ultimately allowing for me to position myself well for a future career in opioid research.