Lauren Rysztak ’18 and Sally Nagia ’18


Robert Leahy is the sheriff in Clermont County, Ohio. In 2017, his ex-wife overdosed on heroin after years of prescription opioid and heroin use. As we can see here, even a law enforcement was not safe from effects of the opioid crisis. Ohio alone saw 2,700 deaths from opioid overdoses just in 20172. The influx of overdoses and death caused Ohio’s morgues to resort to refrigerators on trucks to hold the bodies. From across the country the evidence is clear: there is an opioid epidemic killing tens of thousands of people a year. Now, scientists are wondering, how can prescription painkillers lead to opioid addiction? What effects do these medications have on the body? Is there any treatment for this disease?

As Americans, we rely on drugs to cure any medical condition, from minor injuries and inconveniences to major health diseases and disorders. Because everyone has experienced pain in some form or another we are familiar and comfortable with pain medications such as over the counter pills and drugs used in surgeries. The revolutionary breakthrough of using opioids as pain relieving medications offered a solution to people afflicted with long-term pain. Opioids are drugs with a specific chemical structure, and the use of prescription drugs such as Morphine, Codeine and Oxycodone can cause a dependence on these drugs that spirals into using more potent opioids, like heroin. The over-prescription of these opioid pain medications by doctors, however, has had disastrous and life-changing consequences that no one predicted. Nowadays, the Opioid Crisis is a household term that describes the dire situation in this country of unprecedented levels of opioid, specifically heroin, overdoses and deaths. The Opioid Crisis has plagued Americans in every part of the country and no gender, age, race or socioeconomic status is an exception.

Addiction, generally, can be described as the compulsive seeking out and using of a drug or substance despite knowing the harmful consequences. This can be applied to things other than drugs, such as gambling or sex. Within the brain, addiction has been associated with a chemical used by cells to talk to one another, called dopamine. In a way, we can think of chemicals as letters that cells send to each other to convey information. If you write your friend a letter and send it in the mail, the letter ends up in their mailbox. In this case, you can think of the mailbox as the receptor of the chemical message; similarly, cells have physical receptors on their surfaces. After the letter received, your friend can read the letter and take in the information, similar to how a cell’s receptor receives a chemical message when dopamine binds to it.

In general, dopamine acts to fine-tune our feelings of motivation, which makes sense because people with addictions are very motivated to use their drug of choice, despite its consequences. The brain sees a drug as a reward, and interestingly there is an increase in dopamine during the anticipation of the reward rather than the reward itself, indicating its role in motivation. Dopamine responses are different for everyone. Your friend on a diet may be more motivated to eat a healthy salad when looking at one than you are. Knowing that addiction is tied to motivation this bears the question: are there genes that determine each person’s motivational response and subsequent likelihood for addiction?

Many of you might have had a family member or friend who was warned to stay away from drugs and alcohol because they had a family member with alcoholism or drug addiction and, as they say, “addiction runs in families”. They’re right; addiction does run in families. This is because genes are passed on between generations. Having genes that make you more prone to addiction increases your chances of becoming addicted to a substance compared to a stranger that doesn’t have these genes. How can this be?

Genes are segments of DNA that act as blueprints or instructions or recipes for how the body is structured and how it functions. Each cell in the body is able to read these DNA recipes to  make the proteins, the building blocks of the body. For example, there are genes for brown hair, so if you have those genes your body will make brown hair. There are genes for all of our features, which is a lot. What is interesting is that every cell in the body contains all of the DNA of a person, but only reads the DNA that is necessary for that particular cell. So, an eye cell contains the entire DNA library for the whole body but only reads the genes for eyes and only expresses those proteins for the eye. Now, what matters is not just what kind of gene you have but how much this gene is turned on. This is what is studied in the field of epigenetics.

Now that we better understand how DNA makes up our blueprints, we can turn our attention to the topic of epigenetics. The prefix “epi-“ is derived from the Greek language and means “upon” or “over”. So, you can think of epigenetics as chemical add-ons that that go on top of your DNA sequence. These epigenetic add-ons modify how your DNA will be expressed.

It helps to think of the epigenome as your grandmother’s cookbook, full of pages and pages of classic family recipes. The original recipes can be thought of as your DNA sequence, and these are passed down from generation to generation. However, family members are likely to make some changes to grandma’s original recipes; for example, they might add extra cayenne pepper to turn up the heat in grandma’s special sauce or omit the cilantro in grandma’s salsa. These recipe changes are similar to each person’s epigenetic modifications to their DNA sequence.

Epigenetic changes, like the cayenne additions to grandma’s recipe, have the power to turn genes on or off in our cells. One of the most common epigenetic changes is the addition of a methyl group to our DNA, called methylation. Methylation has many complex effects on genes. However, generally the addition of the methyl group marks a gene to be turned off in the cell. Therefore, genes in a cell that are heavily methylated are not expressed by that cell. Another possible epigenetic change is acetylation. Acetylation generally causes genes to be expressed more. These changes allow for the different cells to use different proteins pertaining to their function, just like how you modify recipes pertaining to your taste. For example, a cell in the skin would not need the genes that code for liver proteins. So, the skin cell will likely have methylation of the liver cell’s genes, which would allow the skin cell’s machinery to ignore the genes that are not needed for its function.

Why epigenetic changes get put onto our DNA sequence is not fully understood. Scientists have found that our environments influence the presence of the epigenetic changes on our DNA. Identical twin siblings are prime subjects for genetic studies because they have identical DNA sequences. However, studies have shown that they each have different chemical add-ons to their DNA. So, their individual recipes will have different ingredients because they interact with their environments differently. For example, if one twin is vegan and the other is not, these dietary differences can affect the presence or absence of epigenetic changes on their DNA sequence. Someone with a vegan diet would prefer to add more vegetables to their dinner recipes, and it’s similar for genetics. These added vegetables are adding to the recipe of DNA and changing the expression of genes. Another factor that can influence the presence or absence of epigenetic changes is the use of opioid prescription drugs.

Many studies have shown how the environment changes the expression of our genes. Dr. Bhushan Kapur has reviewed these studies and summarized their evidence and conclusions. They found that a major gene involved in the study of opioid addiction is the gene for the mu-opioid receptor5. As a reminder, similar to a mailbox, a receptor is a protein on the surface of cells that provides a landing spot for other chemicals, such as opioids. So, the mu-opioid receptor is a type of receptor that specifically binds opioids. When an opioid binds to the mu-opioid receptor, the receptor produces changes inside the cell that lead to the reduction of the feeling of pain.

Usually, this receptor binds endorphins, which are painkilling molecules that are naturally found within our bodies. Endorphins are also considered opioids due to their chemical structures. Because of the uniqueness of our genes, each of our bodies responds differently to painkillers. The same dose of one drug could be too much for one person and not enough for another. When people take opioid painkillers, their bodies change in different ways and can have long lasting effects. After long-term use, the amount of opioid receptors decreases. Because there are less receptors, the same amount of drug has less of a painkilling effect. This individual change is similar to changing grandma’s recipe for medium salsa. After a long time, your taste buds aren’t as sensitive to the spice so you may not think it’s as spicy as when you first tried it. The response of the drug is dulled, like how the spiciness of the salsa is dulled, and then patients need more of the drug to get the same effect.

A similar study by Dr. Hwang and colleagues also relates to the topic of the opioid receptor. These researchers investigated if the amount of receptors present in the cells would change if epigenetic changes were introduced. They found that adding methyl groups to the DNA for the receptor will decrease the amount of the receptors on cells3. This finding is important because the number of receptors present correlates to the amount of pain relief an individual may feel. The more receptors present, the more opioids, such as prescription painkillers, can bind to the receptors, and therefore, the more pain relief and individual will feel. For example, maybe your family loves your grandma’s lasagna so much that she doubles her recipe for the same amount of people in order for everyone to have seconds. The increase in lasagna is similar to the increase in receptors, and your feeling of happiness for having seconds is similar to the increase in pain relief with opioids.

In 2009, another study by the same researchers reported the finding that there is differing amounts opioid receptors in different regions of the brains of mice. The absence of receptors is correlated with DNA methylation4. This finding shows that different regions of the brain use epigenetic changes to turn off genes that they don’t need, similar to the skin cells and liver proteins example explained earlier. Additionally, these researchers noted that there are other proteins (MeCP2) that are responsible for recognizing the methylation of DNA and facilitating the silencing of the mu-opioid receptor gene. As we can see, the process of how epigenetic changes come about is very complex, which allows for differences between individuals to arise.

Building off of previous work about the expression of the opioid receptor, Dr. De-Yong Liang and colleagues describe another major epigenetic alteration of taking opioids: acetylation of the mu-opioid receptor gene. As you may recall, we previously mentioned that acetylation generally causes genes to be expressed more. Taking opioids increases the amount of opioid receptors on cells through acetylation. He introduces an important enzyme, histone acetyltransferase (HAT), which is a protein essential to this process. This protein helps acetylate the genes in DNA, which increases expression of the proteins these genes encode. When the gene for the opioid receptor is acetylated, there will be more production of the receptor. With more receptors the drug can have a bigger effect in the brain leading to a lot more pain relief.

Dr. Liang found that when you inhibit the histone acetyltransferase protein you get fewer opioid receptors in the brain6. Again, with fewer opioid receptors on cells, this will reduce the amount of pain relief. Another effect of decreasing the amount of opioid receptors was that there was a decrease in tolerance and dependence on painkillers6. This shows that an inhibitor of this process could be a treatment for opioid addictions. For example, if you’re watching your weight, you might ask grandma to change her recipe to make the serving size of her lasagna smaller. This is similar to decreasing the amount of opioid receptors. While you may feel hungry after decreasing the serving size for the first time, eventually you won’t feel as hungry anymore. Therefore, decreasing the amount of lasagna decreases your fullness just like decreasing the amount of receptors decreases pain relief.

Lastly, another study found that the epigenetic mechanisms brought on by taking opioids could be reversed. Dr. Egervari with the Friedman Brain Institute in New York showed that opioids increase acetylation (and expression) of a receptor different than the opioid receptor: the glutamate receptor1. What is glutamate and how is it related to opioid addiction? Glutamate is another chemical that allows cells in the brain to talk to each other; a different type of message in a letter. When glutamate binds to its receptor, or mailbox, it increases drug seeking behavior. This is when people are strongly craving drugs and they act in order to get the drug. Similarly, when your grandma increases the amount of sugar in her cookies, they taste amazing and you can’t stop yourself from eating them. Metaphorically, what Dr. Egervari did was decrease the amount of sugar in the cookies, so to speak, making them less desirable and therefore people don’t crave them as much. In reality, he was able to block the increase in the amount of glutamate receptors due to drug use. This blockade also dampens the pain relief effect; similar to what we saw with opioid receptors. In this experiment, animals that were previously addicted to heroin were given chemicals to block increase in the amount of glutamate receptors and therefore did not seek out heroin as much as the other animals that weren’t treated. Although the environment has a large influence on our gene expression, as we can see here, epigenetics can be manipulated to have a behavioral effect.

Why does it matter that the abuse of prescription opioid drugs can change one’s epigenetic make-up? It is because many studies have shown the epigenetic changes can be transmitted to children just like DNA is passed down to children. Therefore, if an individual has struggled with opioid addiction, their own epigenetic make-up would be altered and these alterations can possibly be passed on to the children of this individual.

Most importantly, we hope that this podcast has helped to shed some light on the dangers of using and abusing prescription opioid drugs. Many people may not realize that the use of these drugs can have long lasting effects on their DNA and which genes are on or off. At the same time, it is important to note that prescription painkillers can also have dangerous short-term effects while lingering in the body. For example, the paper by Dr. Kapur and colleagues noted a very sad case of an infant’s death due to overdose of Codeine. In this case, the mother was on Codeine medication for her episiotomy pain and accidentally exposed the infant to the opioid via her breast milk. The breast milk still had active components of the opioid in it and upon ingesting too much of this drug, the infant unfortunately passed away.

As we can see, opioid painkillers provide great relief to those deeply affected by long term pain, however the consequences of misusing and over-prescribing this drug can have not only individual, but generational effects.

References:

  1. Egervari, G., Landry, J., Callans, J., Fullard, JF., Roussos, P., Keller, E., Hurd, YL., “Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target.” Biol Psychiatry. 2017 Apr 1;81(7):585-594. doi:10.1016/j.biopsych.2016.09.015. Epub 2016 Sep 28.
  2. Harlow, Poppy, et al. “City’s Morgues Are Full, Thanks to Opioids.” CNN, Cable News Network, 8 Aug. 2017, www.cnn.com/2017/08/06/health/ohio-heroin-opioid-crisis-morgue-full/index.html.
  3. Hwang, C K, et al. “Evidence of Endogenous Mu Opioid Receptor Regulation by Epigenetic Control of the Promoters.” Molecular and Cellular Biology., U.S. National Library of Medicine, July 2007, www.ncbi.nlm.nih.gov/pubmed/17452465.
  4. Hwang, Cheol Kyu, et al. Journal of Cellular and Molecular Medicine, John Wiley & Sons, Ltd, Sept. 2009, www.ncbi.nlm.nih.gov/pmc/articles/PMC4516510/.
  5. Kapur, BM., Lala, PK., Shaw, JL., “Pharmacogenetics of chronic pain management.” Clin Biochem. 2014 Sep;47(13-14):1169-87. doi: 10.1016/j.clinbiochem.2014.05.065. Epub 2014 Jun 7.
  6. Liang, DY., Li, XQ., Clark, JD., “Epigenetic Regulation of Opioid-Induced Hyperalgesia, Dependence and Tolerance in Mice.” J Pain. 2013 January ; 14(1): 36–47. doi:10.1016/j.jpain.2012.10.005.

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