Profiling Neurological Consequences and Susceptible Populations of Chronic Opioid Use

Project Overview

Our overarching goal for this project was to establish a unique approach to elucidate the neurological consequences of chronic opioid exposure. Synthetic opioids, such as fentanyl, have captured recent attention due to the rapid increase in opioid-related deaths and their high potency. While clinically effective and necessary in certain medical circumstances, the potent neurological effects of these drugs remain a threat to human health when misused. In this project, we leveraged capabilities unique to LLNL to profile the neurological consequences of fentanyl exposure in a human-relevant system. Leveraged capabilities included accelerator mass spectrometry (AMS) to inform relevant dosing, the brain-on-chip (BOC) platform to noninvasively evaluate changes in neuronal function over time, and transcriptomics to profile molecular changes from exposure. In this project, we have successfully established this unique approach and have profiled brain responses to fentanyl in both rodent and human-based systems. Our studies have demonstrated dose-dependent consequences of fentanyl exposure in a rodent system with molecular and functional consequences shown at a high dose (10 micromolar). While no significant alterations to brain function were observed at the lower-dose exposure (0.01 micromolar, analgesic-dose condition), molecular changes using transcriptomics were detected, suggesting that fentanyl rapidly elicits changes in brain plasticity. Similar doses in human-based systems did not result in the same functional changes observed in rodent studies, highlighting the importance of conducting species comparisons and utilization of human-based cell systems when evaluating brain susceptibility to drugs, such as opioids.

Mission Impact

This project will not only advance our capability to predict human health outcomes for opioids, but will also establish an approach to characterize and predict outcomes of exposures to other highly toxic compounds, including biological and chemical threats, treatments, and countermeasures specific to these threats. This research addresses the Laboratory's research and development challenge in the area of chemical and biological countermeasures. This research is in line with other programs in this mission space (e.g., the Forensic Science Center's research on the human exposure signatures for highly toxic materials and computational efforts research into neuronal and receptor models and novel drugs for pain management) and would be of interest to agencies funding these areas. This project also supports the NNSA goal to expand and apply our science and technology capabilities to deal with broad national-security challenges.

Publications, Presentations, and Patents

Lam, D., et al. 2021. "Probing Function in 3D Neuronal Cultures: A Survey of 3D Multielectrode Array Advances." Curr Opin Pharmacol 60, 255-260 (2021); doi: 10.1016/j.coph.2021.08.003.

Lam, D., et al. 2021. "Dose-Dependent Consequences of Sub-Chronic Fentanyl Exposure on Neuron and Glial Co-Cultures." Front Toxicol. 11;4:983415 (2022); doi: 10.3389/ftox.2022.983415.

Lam, D., et al. 2021. "Cellular, Molecular and Functional Changes in the Brain Following Acute and Chronic Fentanyl Exposure." Poster, Society for Neuroscience, Virtual. January 2021.

Enright H.A., et al. "Recapitulating Complex Neuronal-Glia Networks in an In Vitro System for Toxicant Characterization." Poster, NASA Human Research Program IWS 2021, Virtual. February 2021.

Enright, H.A. "Engineered Systems for Toxicity and Countermeasure Evaluation." Presentation IPRAMM Workshop, Virtual. January 2022.

Enright H.A., et al. "Recapitulating Complex Neuronal-Glia Networks in an In Vitro System for Toxicant Characterization." Poster, Chemical and Biological Defense Science and Technology Conference, San Francisco. December 2022.