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  • Hannah Stewart

Opioid Research at the University of Michigan

For the past two years, I have had the opportunity to pursue independent research in Dr. John Traynor’s pharmacology lab, where I am working on a project that aims to develop better and safer medications to treat opioid use disorder (OUD), which is informally known as opioid addiction. 


The use of opioids in their naturally derived form from the opium poppy has been around for thousands of years, originating in ancient Mesopotamia. The roots of the current opioid epidemic, however, did not begin until the 1990s, ultimately caused by the misleading promotion and marketing of OxyContin (oxycodone) by Purdue Pharma. Since the early 2010s, incredibly potent synthetic opioids, such as fentanyl, have continued to drive the opioid epidemic and have resulted in significantly more fatal overdoses than their natural, opium poppy-derived predecessors (UPenn LDI). 


In order to combat the evolving opioid epidemic and other substance use disorders, the Edward F. Domino Research Center (EFDRC) was established within the Department of Pharmacology at the University of Michigan. The EFDRC is named after Dr. Edward F. Domino, a neuroscientist and late faculty member at the University of Michigan who performed the first human studies on ketamine, which is now used in many clinical settings to treat depression. Scientists in the EFDRC are dedicated to understanding the mechanisms behind pain and addiction, and they are pioneering the development of new, safer medications to treat the root causes of pain, OUD, and reverse overdose. 


The EFCRC comprises a core of seven senior scientists working on the science behind addiction. I will highlight three of those scientists and the scientific principles behind drug design efforts to combat the opioid epidemic. The next section will highlight these key scientific principles in the context of opioid pharmacology.


Opioid receptors:

Receptors are proteins that bind a molecule called a ligand outside the cell and relay signals. Opioids are ligands that act at receptors called G-protein coupled receptors, which are proteins that span the cell membrane to connect the inside of the cell to the outside environment. When the ligand binds, a signal is transmitted to the inside of the cell, resulting in a physiological response. 


There are three opioid receptors in the body: the (mu) µ-opioid receptor (MOR), the (kappa) κ-opioid receptor (KOR), and the (delta) δ-opioid receptor (DOR). All abused opioids that drive the epidemic, such as fentanyl, morphine, and oxycodone, bind to MOR. The activation of MOR leads to powerful pain relief but also euphoria, constipation, and respiratory depression. The state of euphoria causes people to become addicted to opioids, and respiratory depression, which suppresses breathing, causes fatal overdoses. KOR and DOR activation leads to other physiological effects, such as mood regulation. 


Endogenous and Exogenous Ligands:

Endogenous ligands are compounds that are naturally made by the body and bind to their receptors. A common endogenous ligand is dopamine, which binds to the dopamine receptor and is released naturally by the body in response to a pleasurable experience. In the case of opioid receptors, endogenous ligands include endorphins and enkephalins, which have the same effects as exogenous opioids like fentanyl and morphine. The body does not produce exogenous ligands. In the case of opioids, these endogenous endorphins and enkephalins are not as potent as their exogenous counterparts and do not provide as powerful pain relief. 


Orthosteric Site:

Proteins are highly complex molecules that can form many interactions with diverse chemical compounds. Therefore, given that there are so many different ways molecules can bind to proteins, we must classify specific sites. The orthosteric site of a protein is where the endogenous ligand binds to exert the natural physiologic effect. Exogenous ligands can also bind to this site and can be split into two categories: agonists or antagonists


Opioid agonists:

Agonists are compounds that bind to and activate a receptor, leading to a physiologic response. In the context of opioids, morphine is an opioid agonist because it binds to and activates MOR, which results in pain relief, euphoria, and respiratory depression. 


Opioid antagonists:

Antagonists are compounds that bind to receptors but do not cause activation of the receptor, therefore blocking the biological response. In the context of opioids, Narcan (naloxone), the most well-known and commonly used overdose reversal treatment, is a MOR antagonist. This mechanism, however, can be overcome if there is comparably more agonist than antagonist, as they will compete to bind to the orthosteric site of MOR. 


Allosteric Site:

Any binding site on a protein that is not the orthosteric site is considered an allosteric site. There can be many allosteric sites on a single protein or receptor. Ligands that bind to allosteric sites, called allosteric modulators, can change the shape of the receptor or some aspect of the receptor signaling pathway, thereby changing the effect that orthosteric ligands have on the biological response. However, allosteric modulators have no intrinsic efficacy by themselves. For example, a compound that acts at an allosteric site could enhance the binding and/or efficacy of morphine, resulting in greater pain relief at a lower dose, and these are known as positive allosteric modulators (PAMs). Conversely, negative allosteric modulators (NAMs) can decrease the binding and/or efficacy of an opioid at the orthosteric site. Mechanisms of allosteric modulation are novel and a unique avenue to explore in modern drug design and are the focus of the projects that I am working on in the Traynor Lab. 


The image below outlines the differences between orthosteric and allosteric sites and how they affect opioid binding. 



This image shows that the binding of an agonist, such as morphine, to MOR has addiction liability due to the euphoric effects of opioids. The red circle represents an antagonist, such as Narcan, which binds to the same site as the opioid agonist but does not lead to activation of the receptor, and its mechanism can be overcome by taking more opioid. The orange triangle represents an allosteric modulator that binds to the allosteric site and can change the shape of a receptor or affect its signaling pattern, changing how an opioid interacts with the orthosteric site.


Dr. John Traynor


Dr. John Traynor is the Director of the Edward F. Domino Research Center and a Professor of Pharmacology and Medicinal Chemistry in the College of Pharmacy. The Traynor Lab is focused primarily on the development of allosteric modulators to improve the safety of opioids. 


A current standard of care for opioid use disorder is the use of longer-lasting antagonists, such as naltrexone. However, these antagonists block both exogenous and endogenous opioids and cause a depressed, sad feeling known as dysphoria, causing patients to quit treatment. In order to combat this issue of patient compliance with treatment, one project in the lab is developing a negative allosteric modulator (NAM) that acts at an allosteric site to reduce the binding and/or efficacy of opioids but not entirely block the orthosteric binding site. Therefore, some of the opioid can still bind, and thus improves patient compliance with treatment by reducing dysphoria, and could serve as a better and safer medication assisted treatment for opioid use disorder compared to current FDA-approved treatments. 


A second project involves the development of a positive allosteric modulator (PAM), which enhances the binding and/or efficacy of an opioid. The aim of this project is to enhance the pain-relieving effects of opioids so a lower dose can be used. Current results demonstrate that PAMs can improve the pain-relieving effects of opioids without enhancing the dangerous and unwanted side effects such as respiratory depression and constipation. 


Dr. Jessica Anand


Dr. Jessica Anand is a Research Assistant Professor of Pharmacology. Dr. Anand is a medicinal chemist by training and focuses on optimizing molecular scaffolds for fentanyl-specific overdose treatments. Fentanyl and other synthetic opioids accounted for 88% of overdose deaths in 2021, and it is increasingly common for other drugs to be laced with fentanyl (CDC). Fentanyl is incredibly potent, and it lasts longer in the body than other opioids. The current standard of care for overdose rescue is Narcan (naloxone), which doesn’t last nearly as long as fentanyl in the brain. Therefore, when Narcan wears off, the fentanyl is still active and no longer competing with the antagonist Narcan and can bind again to MOR. This causes renarcotization, where breathing becomes suppressed again without ingesting any more opioid. Renarcotization is incredibly dangerous, so there is a need to create a longer-lasting opioid antagonist that will be more efficacious than Narcan in reversing a fentanyl overdose. 


Dr. William Birdsong


Dr. William Birdsong is an Assistant Professor of Pharmacology and studies the neural circuits involved in pain and addiction. The Birdsong Lab is particularly interested in learning about how the communication between different parts of the brain is changed by the use of opioids in mouse and rat models. Electrophysiology methods, which explore the electrical activity of neurons and can provide insights into signaling patterns in different parts of the brain, are primarily used. This work enhances our understanding of the fundamental ways in which opioids impact different parts of the brain and can provide insight into how exactly opioids exert their effects and how that manifests in behavioral responses. 


The opioid epidemic requires both a scientific and public health approach to tackle the variety of challenges posed. If you are interested in getting involved in public health initiatives related to the opioid epidemic, I recommend looking into The Lookout Project, which is a student-run organization composed of undergraduates at the University of Michigan aimed at expanding resources and knowledge to destigmatize substance use disorders and aid the Washtenaw County community. You can find more information here.  


References


Centers for Disease Control and Prevention. Drug Overdose Deaths. https://www.cdc.gov/drugoverdose/deaths/index.html.


Weiner, J. (2022, January 11). The Origins of the Opioid Epidemic. https://ldi.upenn.edu/our-work/research-updates/the-origins-of-the-opioid-epidemic/

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