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How Do Opioids Affect Brain Chemistry? (Serotonin & More)

Table of Contents

Opioids affect brain chemistry in a variety of ways, triggering feelings of euphoria, enhancing relaxation, and lessening the experience of pain. Over time, they cause imbalances in brain chemistry that lead to dependence.

What Are Opioids? 

Opioid drugs have been used for medicine and recreation for thousands of years. It started with people collecting sap from the opium poppy and has progressed to the modern epidemic of prescription and illicit synthetic opioid addiction and overdose.

This class of medication is often referred to as narcotics, which comes from the Greek word for “stupor.”

Opioid drugs dull the senses, induce relaxation, slow breathing, and digestion, and relieve pain. Many narcotics are prescription drugs, used to dull moderate to severe pain on a short-term basis after surgery or an injury. Others are abused for the relaxing euphoria and emotional painlessness that they induce.

Regardless of their purpose, opioids impact the brain in similar ways. They can lead to substance abuse, addiction, and even overdose.

History of Opioid Abuse

There have been several waves of opioid addiction crisis since morphine was first synthesized in the 19th century. Morphine became an important medical treatment for pain, but it also led to a significant addiction epidemic. This led to the development of heroin.

Heroin abuse led to a serious crackdown on the drug with the Controlled Substances Act (CSA) in the 1970s, but in the 1990s, pharmaceutical companies developed new opioid painkillers and advocated for wider prescribing of these medications to treat less severe or permanent levels of pain. With more prescriptions for new opioid painkillers, more people had access to these drugs, which has been part of a resurgence in opioid abuse in the United States.

With new approaches to medical treatment for addiction, the process of detoxing from opioids and how behavioral treatment works in rehabilitation is better understood. Knowing how these drugs affect brain chemistry, whether they are prescription or non-medical, can help clinicians, those struggling with opioid addiction, and their friends and family understand how best to approach treatment.

How Opioids Work in the Brain

Opioid drugs bind to the opioid receptors in the brain, mimicking how the brain’s naturally produced opioids (endogenous opioids) work. However, synthetic opioid drugs are stronger than the brain’s natural opioids. How they change brain chemistry to relieve pain  effectively can be very harmful.

For example, low doses of opioids might make you feel sleepy like you did not get enough rest the night before. High doses, however, change your breathing rate and heartbeat. The leading cause of death in an opioid overdose is irregular, depressed, or stopped breathing, causing oxygen deprivation.

Opioid receptors are found primarily in the cortex, limbic system, and brain stem. These areas release neurotransmitters to reward the body when certain foods, drinks, and “potential mates” trigger the brain’s reward system. Opioids are part of how appetite is regulated by the brain, and there is some evidence showing that sexual desire is wrapped in this reward/opioid-release process as well. 

Natural vs. Artificial Opioids

A 2018 study conducted by researchers at UC San Francisco found that neurons reacted differently to endogenous opioids, produced naturally by the brain, than they did to artificial opioids. Opioid neurotransmitters produced by the brain itself are stimulated by exercising, which can lead to a “natural high” like the euphoria reported by marathon runners.

While both artificial and natural opioids in the brain bind to neurons’ opioid receptors, scientists had believed for decades that the two chemicals triggered similar responses. Both types of opioids were believed to attach to receptors on the surface of the neuron, where they are then taken inside the cell by endosomes. Once the process of moving inside the neuron occurred, however, opioids were not believed to trigger signals from this location. However, the research team discovered that opioid receptors remain active while they have moved inside the neuron, and the endosome sustains the signal between cells.

The new study found that synthetic opioids activated receptor cells inside neurons too, and the locations of these activated intracellular receptors were different when they responded to natural opioids compared to artificial opioids. The Golgi apparatus, which is inside neurons, is activated by artificial opioids but not by natural opioids, which may explain the strength and stamina of narcotic drugs’ effects on the brain.

Additionally, morphine-based synthetic opioids were found to cross neuron cell membranes without binding to receptors or entering endosomes, going directly to the Golgi apparatus. Natural opioids completed their “digestion” process within a neuron in about one minute, but synthetic opioid drugs were found to stimulate neurons in 20 seconds.

This effect could be part of why artificial opioids, from opium to heroin to fentanyl, were treated as a more rewarding experience by the brain compared to natural opioids. They bypass how the neuron works to trigger effects and side effects much faster than the naturally produced opioids did. This suggests that artificial opioids can produce effects that natural opioids do not.

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What Are the Short-Term Effects of Opioids on Brain Chemistry? 

When you take an opioid drug as a prescription medication to treat pain, it is processed through your digestive system, and it enters the bloodstream at a controlled speed. The chemical then enters the brain from the bloodstream and binds to opioid receptors on neurons involved in pain signaling. By suppressing this signaling, opioids help you feel less pain, which you may otherwise feel after surgery, being injured, or developing a symptom of a chronic illness.

However, the opioid will also trigger effects: 

  • In the limbic system, which manages emotions like pleasure and happiness
  • In the brain stem, which regulates breathing, so your breathing could be slowed
  • Involving the heart rate, which is managed by the brain stem

Mental effects from a potent opioid drug, like heroin, include:

  • Initial euphoria, or feeling happy and relaxed
  • Fatigue
  • Clouded thinking or cognitive “fogginess.”
  • Depression or persistent sadness
  • Short-term memory trouble

These effects wear off at different speeds, depending on how rapidly the specific opioid is designed to metabolize out of the body. For heroin, the mental effects (especially euphoria) may only last a few minutes; however, the physical effects like painlessness and breath suppression can last for hours.

Unfortunately, many people seek the immediate mental effects of these drugs, which can lead to taking another dose as soon as the first high wears off. This will lead to overdose very quickly.

What Are the Long-Term Effects?

Some studies have found that long-term exposure to opioid drugs can change gene expression. In animal studies, repeated exposure to alcohol or opioids produced downregulation of opioid peptides in areas of the brain after the animals were no longer given these substances. These same studies found that the same basic areas were upregulated when chronically exposed to stimulant drugs.

Downregulation occurs when a cell decreases the quantity of a cellular component, like a protein or RNA, in response to an external variable, like a drug. In contrast, an increase in this component in a cell, in response to external variables, is called upregulation. One example of downregulation for neurons is a reduction in the number of neurotransmitter receptors on the outside of the cell.

Animal studies on opioids indicate that this downregulation process may strip neurons of opioid receptors. With the 2018 study, this suggests that natural opioids produced by the brain will not be as effective, while synthetic opioids can continue to work.

Since the brain needs opioids for some processes, causing a reduction in receptors on neurons can show why the brain becomes chemically dependent on synthetic narcotics to manage pain, appetite, relaxation, and happiness. It suggests why withdrawal, while not life-threatening, can be tough without chemical management from medication-assisted treatment (MAT).

Managing Brain Chemistry to End Opioid Addiction

Without help from MAT, withdrawal symptoms from opioids can include the following:

  • Insomnia
  • Anxiety
  • Irritability and restlessness
  • Intense cravings for the drug
  • Depression

There are many physical symptoms of withdrawal from opioids as well. The combination can be incredibly uncomfortable. Without help, you are at high risk of relapsing back into opioid abuse. Getting help with medical professionals who use MAT to taper your body off opioid dependence is the first step in overcoming opioid abuse.

Buprenorphine and methadone are the primary medications prescribed to people who struggle with opioid addiction. These drugs bind to opioid receptors — buprenorphine is a partial opioid agonist, while methadone is a very long-lasting full opioid agonist — and can ease cravings and withdrawal symptoms without causing euphoria. An overseeing physician can then step down, or taper, the body off dependence on opioids.


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(March 21, 2018). What are Opioids and Why are they Dangerous? Mayo Clinic. Retrieved March 2019 from

Physiological Review. (2009 October) Reward Processing by the Opioid System in the Brain. Le Merrer, J. Becker, J., KATIA Befort, K., and Kieffer, B. Retrieved from

University of California San Francisco, (2018, May 10) Body’s 'Natural Opioids' Affect Brain Cells Much Differently than Morphine, Bai, N., Smith, D. Retrieved from

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