The Endogenous Opioid System: Your Body’s Natural Pain Reliever?

March 16, 2021

Written by: Lindsay Ejoh

Let’s go back in time. Imagine you are seven years old again, running through the kitchen for a sweet treat from the cookie jar. Too excited, you don’t notice a box on the ground, and trip over it, scraping your knee. Your mother sees you crying in pain and kisses the wound to make it better. Surprisingly, you feel better almost instantly. Is your mom a miracle worker, or do you have your nervous system to thank? 

It turns out your mom is not the miraculous healer she seemed to be. When you are in pain, your brain can provide relief by performing “top-down” modulation of pain signals, during which projections from the brain are sent down to the spinal cord in order to alleviate the perception of pain1. In 1977, scientists discovered one such pathway when they found that electrical stimulation of the periaqueductal gray, a brain region now known to be involved in top-down pain modulation, relieved pain so dramatically that doctors could perform invasive surgeries without the patient feeling any pain2. Your brain can also provide relief from acute pain in life-threatening situations. Imagine you are walking through the woods, and see a bear running towards you. You run, trip over a branch, and bend your ankle on the way down. Despite this, you are still able to stand up and continue to run despite having injured your ankle. In this situation, your brain realizes you are in serious mortal threat, and suppresses pain in order to increase your chance of survival by fight or flight. This is one example of your body using your endogenous (internal or natural) opioid system to relieve pain without the help of medication

What does “top-down modulation” look like in the nervous system? Neurons in the brain send projections down into the spinal cord, where they release opioid molecules onto pain neurons in the spinal cord3. This inhibits the activity of these pain neurons, preventing pain information from travelling up to the brain, essentially “relieving pain.”

How similar are endogenous opioids and opioids taken as medication?  Common medicinal opioids include morphine, codeine, fentanyl, oxycodone, and others. Whether taken in the form of medication or released naturally by the body, opioid molecules bind to the same specialized receptors on neurons in order to alleviate pain3. Opioid receptors are located all over the nervous system- including the gut, which is why taking opioids as medication can lead to harmful side effects throughout the body. These side effects­­ of medications include difficulty breathing, constipation, nausea, vomiting, and mood swings. 

Opioid receptors are also expressed in high quantities in addiction-related regions of the brain, and when taken over a prolonged period, often leads to tolerance and addiction. Opioid misuse and abuse is a serious issue in the United States, affecting 1.6 million people a year4. Forty-eight thousand people died from opioid overdose in 2020 alone! The National Institutes of Health have coined this the “opioid epidemic”, and are currently funding research to address these issues in two ways: improving existing opioid therapies to reduce harmful side effects, and taking advantage of the endogenous opioid system to create therapies to relieve pain that are less likely to result in addiction and/or overdose. 

For example, fentanyl is an extremely effective pain reliever, but is a respiratory depressant and causes difficulty breathing, making it dangerously easy to overdose on. Scientists have found that giving another drug alongside that acts on the serotonin receptor (5-HT4) can stabilize breathing while still allowing for efficient pain relief 1. Unfortunately, fentanyl is still an opioid, and other harmful side effects will persist. As an alternative, scientists are taking advantage of the endogenous opioid system with deep brain stimulation therapy to treat pain6. Electrically stimulating the periaqueductal gray has shown to be moderately effective, but also comes with its own risks, including infections, seizures, and intracerebral hemorrhages. Further research must be conducted to improve therapies for pain relief in order to treat chronic pain disorders, and curb the rampant opioid epidemic. 


  1. Holden, J. E., Jeong, Y., & Forrest, J. M. (2005). The endogenous Opioid system and Clinical pain management. AACN Clinical Issues: Advanced Practice in Acute and Critical Care, 16(3), 291-301. doi:10.1097/00044067-200507000-00003
  2. Hosobuchi, Y., Adams, J. E., & Linchitz, R (1978). Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Survey of Anesthesiology, 22(3). doi:10.1097/00132586-197806000-00029
  3. Corder, G., Castro, D. C., Bruchas, M. R., & Scherrer, G. (2018). Endogenous and exogenous opioids in pain. Annual Review of Neuroscience, 41(1), 453-473. doi:10.1146/annurev-neuro-080317-061522
  4. A. (n.d.). What is the U.S. opioid epidemic? Retrieved March 09, 2021, from
  5. Young, R. F. (1997). Deep-brain stimulation for the treatment of chronic pain. Current Review of Pain, 1(3), 182-191. doi:10.1007/bf02938166

Cover Image from Unsplash user Sam Burris

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