Visualizing addiction: How new research could change the way we fight the opioid epidemic

New research from a Max Planck Florida Institute for Neuroscience researcher could transform how we understand the way opioids affect the brain. Despite significant discussion surrounding the ongoing opioid crisis, current understanding of how opioids function in the brain is quite limited. This is primarily due to challenges in observing and measuring opioid effects in the brain in real-time. However, a recent technological breakthrough, led by Dr. Lin Tian and her research team and collaborators, recently published in Nature Neuroscience, has overcome these limitations and is set to transform how scientists study opioid signaling in the brain.

What do we know about opioid signaling?
Pharmaceutical opioids, such as morphine and oxycodone, and illicit opioid drugs like heroin, affect the brain and body by binding to opioid receptors on the surface of cells in the nervous system. These receptors normally respond to naturally-produced chemicals that are released in your brain, called endogenous opioids, including endorphins, enkephalins, and dynorphins. Released in response to pleasurable activities such as laughter, sex, and exercise and aversive activities like injury and trauma, these chemicals bind opioid receptors and reduce the ability of neurons to receive and transmit signals. These cellular effects ultimately lead to the cognitive and behavioral effects associated with opioids, including positive feelings, pain relief, and addiction.

Challenges in understanding opioid signaling
Numerous questions remain about how these behavioral effects are caused by opioids and whether it is possible to harness specific opioid properties such as pain relief without undesirable effects, such as addiction. The opioid scientific literature is extensive and has confirmed that targeting the opioid system is of clinical interest – not only for pain management but also, more recently, for the treatment of mental health disorders such as anxiety and depression. Development of therapeutics that can target these health challenges while preventing the tragedy of the current opioid epidemic requires further understanding of the diverse effects of opioids in the brain.

The diversity of opioid effects on the brain is driven by more than 20 different opioid chemicals produced in the brain and more than 500 different synthetic opioids. Most of these different opioids interact with all three types of opioid receptors with different strengths. Their varied effects depend on the concentration of opioid, the specific receptors present and the brain circuits involved.

“Efforts are underway to harness various therapeutic properties of opioids by targeting specific receptor actions and brain circuits to develop more effective and safer therapeutics. However, these efforts have been hampered by our inability to measure diverse opioid signaling in real-time in the brain effectively,” said Dr. Tian.

New technology opens door to understanding opioids in brain
Through a massive effort developing and testing over 1,000 variants, Dr. Tian’s team has optimized highly-sensitive biosensors based on the three opioid receptors. These biosensors, originally developed while Tian was at the University of California, Davis, emit fluorescence upon opioid binding to the sensor and turn off when the opioid is no longer there. The biosensors, therefore, serve as a proxy for opioid binding to specific opioid receptors. Introducing these sensors into the brain of an animal provides a way to visualize opioid signaling across the brain in real-time.

“The power of this new technology is that we now have the tools to understand the natural opioid system in the brain, including how to distinguish between different opioid effects. We can track endogenous opioid release in real-time, triggered by both reward and aversion and see the differences in opioid signaling in different brain circuits.”

Dr. Tian’s team has already been sharing these new tools widely to accelerate the impact this new technology will have on the understanding of opioids.
 

Original Publication Information: 
Title: Unlocking opioid neuropeptide dynamics with genetically-encoded biosensors  
Authors: Chunyang Dong, Raajaram Gowrishankar, Yihan Jin, Xinyi Jenny He, Achla Gupta, Huikun Wang, Nilüfer Sayar Atasoy, Rodolfo Flores-Garcia, Karan Mahe, Nikki Tjahjono, Ruqiang Liang, Aaron Marley, Grace Or Mizuno, Darren Kirin Lo, Qingtao Sun, Jennifer L. Whistler1, Bo Li, Ivone Gomes, Mark Von Zastrow, Hugo A Tejeda, Deniz Atasoy, Lakshmi A Devi, Michael R. Bruchas, Matthew R. Banghart, Lin Tian   
Journal: Nature Neuroscience
Link: https://www.nature.com/articles/s41593-024-01697-1
 

About the Tian Lab
Dr. Lin Tian started as Scientific Director of the Max Planck Florida Institute in October 2023. Before this, she was the Professor and Vice Chair in the Department of Biochemistry and Molecular Medicine at the University of California Davis School of Medicine, where her work on the development of the biosensors began and continue to remain as an adjunct professor. Dr. Tian’s research focuses on engineering optical sensors for monitoring and controlling neural circuitry in living, behaving animals. These new imaging techniques have greatly impacted the field of neuroscience, facilitating new types of biological experiments performed to address previously intractable questions. Her scientific contributions have earned her international recognition as a leader in neuroengineering, with a focus on generating new molecular tools to understand and repair the brain. Research in the Tian Lab focuses on technological innovation and interdisciplinary collaboration to uncover the connection between brain function and behavior in healthy and diseased states, such as neurological and psychiatric disorders. Dr. Tian’s goal is to find treatments for neuropsychiatric diseases that free patients from debilitating symptoms without the unwanted properties characteristic of existing therapeutics.

About the Max Planck Florida Institute for Neuroscience
The Max Planck Florida Institute for Neuroscience, a not-for-profit research organization, is part of the world-renowned Max Planck Society, Germany’s most successful research organization with more than 80 institutes worldwide. Since its establishment, 31 Nobel laureates have emerged from the ranks of its scientists including six in the last four years alone. As its first U.S. institution, MPFI provides exceptional neuroscientists from around the world with the resources and technology to answer fundamental questions about brain development and function. MPFI researchers employ a curiosity-driven approach to science to develop new technologies that make groundbreaking scientific discoveries possible. For more information, visit mpfi.org.

This research was supported by National Institutes of Health including the NIH BRAIN Initiative (U01NS103522, U01NS120820 and U01NS113295), National Institute of Drug Addiction (R37DA033396, R61DA051489, K99058709) and the National Institute of Mental Health (ZIA-MH002970-04) and the National Institutes of Health grants (DA008863, DA058300 and DK126740). This content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.