How the Body's Own Opioid Peptides Regulate Pain and Contribute to Opioid Addiction | Research

The takeaway

This review examines how the four endogenous opioid peptide systems (β-endorphins, dynorphins, enkephalins, and nociceptins) regulate pain and how their disruption by exogenous opioid use contributes to addiction.

4 endogenous opioid peptide systems
β-endorphins, dynorphins, enkephalins, and nociceptins each signal through distinct receptors to regulate pain, mood, and reward — all disrupted by chronic pain and opioid drug use

What the researchers found

The review maps the four endogenous opioid peptide systems and their roles:

1. μ-opioid receptor (MOPR) / β-endorphins — primary mediator of pain relief and euphoria; the main target of opioid drugs

2. κ-opioid receptor (KOPR) / dynorphins — involved in stress responses and dysphoria; may contribute to negative emotional states during withdrawal

3. δ-opioid receptor (DOPR) / enkephalins — modulates mood, motivation, and pain; potential target for non-addictive analgesics

4. Nociceptin receptor (NOPR) / nociceptins — regulates pain sensitivity, anxiety, and stress responses

Key insight: chronic pain itself alters endogenous opioid system function, and these alterations — combined with the effects of exogenous opioid use — create a self-reinforcing cycle that increases the likelihood of developing opioid use disorder.

Why it matters

The opioid crisis has killed hundreds of thousands of people, yet pain management remains a critical medical need. The endogenous opioid peptides represent the body's own sophisticated pain management system — understanding exactly how chronic pain and opioid drugs disrupt these systems could reveal safer therapeutic strategies. For example, targeting the δ-opioid receptor with enkephalin-like drugs might provide pain relief without the euphoria and addiction risk associated with μ-receptor targeting drugs.

How the study worked

This is a comprehensive narrative review synthesizing decades of research on endogenous opioid peptide function, expression, pharmacology, and regulation. It covers basic science, animal models, and clinical observations on pain, opioid use, and addiction.

What this study cannot tell us

As a narrative review, it does not present original experimental data or systematic methodology. The endogenous opioid literature is vast, and the review necessarily simplifies some aspects. The relationship between endogenous opioid system alterations and OUD development is supported by strong evidence but establishing direct causation in humans remains challenging. Individual genetic variation in opioid receptor expression and function adds complexity not fully addressed.

How to read the evidence

This is a narrative review of extensive existing literature spanning basic science, animal models, and clinical observations. It provides a comprehensive overview but does not add new evidence. The underlying research varies from robust receptor pharmacology studies to observational clinical data.

When this study was published

Published in 2022, this review reflects the current understanding of endogenous opioid systems in the context of the ongoing opioid crisis, incorporating recent advances in receptor pharmacology and addiction neuroscience.

The bigger picture

The opioid peptide system was one of the earliest and most impactful discoveries in neuropeptide biology. The identification of endorphins, enkephalins, and their receptors in the 1970s was a landmark achievement. Today, this foundational knowledge is being leveraged to develop biased agonists (drugs that activate pain relief without euphoria), peripherally restricted opioids (that work outside the brain), and non-opioid analgesics guided by understanding of how endogenous systems regulate pain. This review connects decades of basic science to the urgent clinical problem of opioid addiction.

Questions still open

Could drugs targeting the δ-opioid receptor or nociceptin receptor provide effective pain relief without the addiction risk of μ-opioid drugs?
Can biomarkers of endogenous opioid system dysfunction identify patients at highest risk for developing OUD before prescribing opioids?
Would restoring endogenous opioid peptide levels through gene therapy or peptide supplementation help treat chronic pain or opioid addiction?

Common questions

What are endogenous opioid peptides and why does the body make them?

Endogenous opioid peptides — including β-endorphins, enkephalins, dynorphins, and nociceptins — are natural painkillers produced by the body. They bind to opioid receptors in the brain and nervous system to reduce pain, regulate mood, manage stress, and control reward responses. They are released during exercise (the 'runner's high'), eating, social bonding, and in response to injury. These peptides evolved to help the body manage pain and stress without external drugs.

Why do opioid drugs cause addiction if the body already makes its own opioids?

The key difference is dose and timing. Natural opioid peptides are released in small, precisely controlled amounts at specific locations in the brain. Opioid drugs flood the entire system with much larger amounts, overwhelming the receptors and producing intense euphoria. The brain responds by reducing its own opioid peptide production and decreasing receptor sensitivity. This means without the drug, the person feels worse than before — both more pain and more emotional distress — creating a powerful drive to keep using.

Read the original research

Endogenous opioid systems alterations in pain and opioid use disorder.

Frontiers in systems neuroscience, 16, 1014768

View on PubMed ↗Publisher’s paper ↗

Citation

Higginbotham, Jessica A; Markovic, Tamara; Massaly, Nicolas; Morón, Jose A. (2022). Endogenous opioid systems alterations in pain and opioid use disorder.. Frontiers in systems neuroscience, 16, 1014768. https://doi.org/10.3389/fnsys.2022.1014768