The National Institute on Drug Abuse (NIDA) has awarded Jordan McCall, PhD, associate professor of anesthesiology at WashU Medicine and the Center for Clinical Pharmacology, a five-year, $3,414,110 grant to study how fentanyl disrupts a brain region called the locus coeruleus and drives relapse to opioid use.
The locus coeruleus is best known as a source of the brain’s natural pain relief, but growing evidence suggests chronic opioid exposure can transform it into a driver of drug seeking and negative mood. McCall’s team has found that these neurons have a natural ‘off switch’ — receptors that respond to the body’s own opioids — which normally keeps drug reward in check. When that off switch weakens, it may make relapse more likely.
Using fiber photometry, optogenetics, and receptor rescue techniques in mice, the McCall Lab, in collaboration with the Al-Hasani Lab and Moron-Concepcion Lab, will examine how this loss of natural inhibition after long-term fentanyl use affects brain circuits tied to negative mood and cravings. The team will also test non-opioid strategies to restore that inhibition and reduce blunt cue-triggered relapse.
This work complements research by McCall Lab postdoctoral researcher Lea Becker, PhD, who recently received a K99/R00 award to study how fentanyl alters the noradrenergic system to affect myelination in the forebrain. Together, the projects will provide a broader understanding of how fentanyl changes noradrenergic signaling and function across the brain.
With tens of thousands of Americans dying of synthetic opioid overdoses each year, the findings could point toward new, non-opioid targets for treating opioid use disorder and preventing relapse.