Drew Casey ’20 and Lucas DeYoung ’21


Epigenetic Mechanisms of Drug Addiction in the Midst of the Opioid Crisis

Prescription painkillers are vital for proper medical treatment for patients who endure chronic or acute pain. Opioids in particular are commonly prescribed due to their effectiveness in treating pain, however these drugs are known to be highly addictive and can have terrible effects if overused or abused. Opioids such as Vicodin, morphine, and fentanyl are known to be addictive and can lead to severe consequences when mistreated. How these drugs and the addiction it causes affect the brain is not yet fully understood, however every year we learn more and come closer to painting a full picture of the way the brain is affected by these drugs. Recent studies suggest opioid consumption leads to changes in DNA and DNA storage systems that have direct, long-lasting effects on brain circuitry as well as behavior.  These DNA modifications, specifically those located in brain cells, have spawned an increasing amount of research which has led to the development of the field of neuroepigenetics.  The field of neuroepigenetics looks at these DNA modifications that have been caused by life choices and the environment, and how they affect cell structure and function.  These studies will potentially give us a better understanding of how and why opioids cause the effects they do, and hopefully inspire ways in which they can still be used without their detrimental effects.

The effects of opioid addiction within US communities both small and large are prominent and lasting.  The United States prescribed almost twice as many opioids as any other country in 2016, with illicitly-sold drugs such as heroin greatly exacerbating the problem.  Drug overdose deaths in the United States have increased every year from 1999 to 2017, which has been greatly influenced by the overreliance on prescription opioids by the general public4.  Understanding how and why these problems arise and the epigenetic mechanisms that underlie these issues can create a healthy respect for the effects of opioids and lead to greater caution in order to prevent the problem from becoming any worse.

Particular portions of the brain have been directly associated with major changes to the structure of DNA due to opioid use, which causes the brain to act differently.  One (but not the only) major center where we see these factors is in the nucleus accumbens (NAcc), located towards the lower central portion of the brain (in red on the figure to the right). NAcc activity has been associated with natural reward pathways that are activated not only by opioid consumption but also by other rewarding behaviors such as calorie-dense food and sex.  The NAcc is particularly influential in creating a person’s motivation, as well as the formation of habits, which explains its connection to motivational and habitual behaviors associated with addiction5 Direct changes to this brain region are one major reason for the addictive properties of painkilling drugs. Studies have shown that long-term opioid use decreases the activation of pleasurable sensations in the NAcc that we would receive from sources other than the drug, while at the same time increasing activation due to opioids1. This creates a dependency on the drug since it becomes one of the only ways to produce a pleasurable activation of NAcc neurons. This, in turn, is what creates the addictive effects of opioids, as chronic users only have one manner to activate this pleasure epicenter of the brain.

When considering how opioids act and how they may affect the genome of an individual, it is crucial to first understand what an epigenetic modification is.  Within each and every cell of the human body, including brain cells, is a full set of DNA that makes up the genome. Different cells utilize different portions of the genome in order to carry out the appropriate functions of that cell, such as allowing muscles to move our body, blood to take oxygen to cells, or neurons to carry information throughout the brain.  Many of These differences are maintained by how the DNA is stored within the nucleus of a cell.  DNA is an extremely long molecule, so long in fact that if the DNA within a single cell were stretched out to its full length it would be about 3 meters (10 feet) long.  In order for DNA to fit into the cell, it is condensed and wrapped around spherical proteins called histones.  The structure created by histones and DNA wrapped together is known as chromatin.  However, histones serve as much more than simply a storage system.  Histones are also used by the cell to decide which portions of the DNA should be activated or inactivated which allows that cell to carry out the appropriate function.  Certain molecules can attach themselves to histones, which changes how tightly the DNA is wrapped around them which varies chromatin structure and density.  More open structures allow cellular mechanisms to reach portions of the DNA, which enables the code to be read and serves to activate that portion of code within the entirety of the cell, increasing the function encoded within that region of DNA.

One of the most common modifications is histone methylation, which is the addition of a single carbon along with three hydrogen atoms to one of the spherical histone proteins that DNA is wrapped around.  Depending on the location of the added methyl group on the histone, it can increase or decrease the amount of gene activation by condensing or opening the DNA code in that, area which can change how the cell functions due to changes in how the cell reads the DNA.  Considering that all opioids contain methyl groups that can be metabolized and attached to histones, these drugs can have many unknown epigenetic effects that alter brain function and human behavior.  Furthermore, opioids may affect enzymes that are necessary for adding these methyl groups to histones, which can also change the methylation state at DNA sites that would be used for cell function.

Another important histone modification is the acetylation of histones. Acetylation is typically associated with an increase in gene expression. These acetylation tags are often studied using histone deacetylases (HDACs) which is the machinery that removes acetylation tags in the cell and therefore decreases gene expression. Increasing the expression of HDAC’s within a cell removes acetylation tags and essentially ”shuts down” particular genes by closing the histone proteins and reducing the accessibility of DNA at these targets. This allows the cell to deactivate unnecessary or unused portions of the genome, which can then be stored more efficiently and decrease the potential for unnecessary gene expression.

One common focus of recent studies looks at the genetic region labeled G9a, which codes for a protein known as a histone methyltransferase enzyme. Histone methyltransferases add methyl groups to specific histones in the nucleus accumbens.  G9a activity was found to decrease in response to morphine administration, which decreases the number of methyl groups on histones. This leads to greater expression of genes in the reward pathway potentially related to neural plasticity and addictive tendencies6. In contrast, the same study increased the function of this enzyme within mice, which increased histone methylation. As predicted, tolerance to these drugs was extended, decreasing the addictive tendencies that were otherwise initiated by morphine.  This was supported by the behavioral aspect of the study.  Mice were treated with a DNA insertion that increased G9a activity and then compared to mice given a placebo treatment that leaves G9a functioning at normal levels.  Mice with hyperactivity of G9a showed decreased preferences for morphine when given the opportunity to self-administer the drug versus the saline administration.  Morphine was shown to decrease G9a activity, which shows a potential mechanism in which morphine increases the addictive behavior of mice through epigenetic mechanisms, including decreasing histone methylation through inhibition of the G9a methylation enzyme.  This finding helps to demonstrate the dangers that opioids pose to those who rely on them for pain therapy and the likelihood that their consumption leads to addiction through neuroepigenetic mechanisms.

Another gene shown to be associated with the addictive effects of morphine is the SIRT1 histone deacetylase. SIRT1 is shown to also affect the genetic structure of cells located within the NAcc, which means that acetyl groups located on histones are being removed more frequently, decreasing genetic accessibility. SIRT1 was shown to increase in the presence of morphine, presumably to increase the reward potential induced by the drug. Ferguson et al. followed up these findings by increasing SIRT1 expression within the NAcc and observing the effects. They found that increasing SIRT1 also increased reward behavior within mice, tying the increase of SIRT1 with an increase in addictive qualities of morphine3. Glancing between the effects of SIRT1 and G9a, it becomes clear that the effects of chronic opioid use on these two proteins lead to an opposite effect on DNA: one causes further activation of genes while the other is responsible for deactivating. This shows that multiple genetic regions are important for increasing the addictive effects of opioids. It is not a single genetic mechanism that causes a reward increase within the NAcc, but the use of multiple genetic elements all contributing to the detrimental addictive properties associated with these drugs. Several different processes are kicked into action in the presence of opioids, all of which contribute to the reward increase seen in chronic opioid use. This shows that it is not a genetic fluke causing these changes, but a purposeful change by the brain to increase the pleasurable sensations brought about by the drug by increasing the pleasure it brings while also decreasing the pleasure from other sources.

The mechanisms that drive opioid addiction are profound and enduring, forming lasting changes to DNA expression within the brain. Drug-seeking behavior is driven by these changes, making it crucial that we go about educating the general public as much as possible so that they understand that although these drugs can be useful, they are also dangerous. Countering the increasing cases of overdose and addiction, especially within the United States, has become an important responsibility for those within the medical and research fields. The ways in which these drugs influence neuroepigenetics can help us paint a clearer picture of the most effective ways to move forward and perhaps enlighten others to create treatments or additives to already used drugs that decrease their harmful effects.

References

  1. Browne, Caleb J., et al. “Epigenetic Mechanisms of Opioid Addiction.” Biological Psychiatry, July 2019, 10.1016/j.biopsych.2019.06.027. Accessed 20 Aug. 2019.
  2. Egervari, Gabor, et al. “Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target.” Biological Psychiatry, vol. 81, no. 7, 1 Apr. 2017, pp. 585–594, www.sciencedirect.com/science/article/abs/pii/S0006322316328335, 10.1016/j.biopsych.2016.09.015. Accessed 28 Mar. 2020.
  3. Ferguson, Deveroux, et al. “Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action.” The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, vol. 33, no. 41, 2013, pp. 16088–98, www.ncbi.nlm.nih.gov/pmc/articles/PMC3792451/, 10.1523/JNEUROSCI.1284-13.2013. Accessed 21 Jan. 2020.
  4. Lopez, German. “The Opioid Epidemic, Explained.” Vox, Vox, 3 Aug. 2017, www.vox.com/science-and-health/2017/8/3/16079772/opioid-epidemic-drug-overdoses.
  5. McFalls, Ashley. “U-M Weblogin.” Weblogin.Umich.Edu, May 2018, search-proquest-com.proxy.lib.umich.edu/docview/2082376761/fulltextPDF/7C2FF7B414774336PQ/1?accountid=14667. Accessed 28 Mar. 2020.
  6. Sun, HaoSheng, et al. “Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens.” Journal of Neuroscience, vol. 32, no. 48, 28 Nov. 2012, pp. 17454–17464, www.jneurosci.org/content/32/48/17454, 10.1523/JNEUROSCI.1357-12.2012. Accessed 28 Mar. 2020.

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