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The endogenous opioid system

In this article, Drs Seung Cheol Kim and Fausto Morell-Ducos explore the body's innate pain-relieving system, the endogenous opioid system
3D rendering of microscopic view of mu-, delta- and kappa-opioid receptors
© Shutterstock

In the last step, you touched upon endogenous opioid peptides. In this step, Dr Seung Cheol Kim, Pain Medicine Fellow at the Royal National Orthopaedic Hospital, and Dr Fausto Morell-Ducos, Consultant in Anaesthesia and Pain Medicine at UCLH, describe the endogenous opioid system in more detail.

You may have sustained a sports injury only to realise its full extent some time after the game. Or you may have wondered why, immediately following traumatic accidents like road traffic collisions, people sometimes do not experience pain from severe injuries until much later. Our body harbours a sophisticated internal pharmacy which may go some way to explain this.

The four opioid receptors we mentioned in Step 2.6 – mu, delta, kappa and nociceptin/orphanin-FQ (also known as MOP, DOP, KOP and NOP) – are not only activated by opioids administered as medication (exogenous opioids) but also by neurotransmitters produced by the body within the central nervous system (CNS) – these are the endogenous opioids.

This network of neurons with opioid receptors activated by endogenous opioids is known as the endogenous opioid system (EOS). Apart from being present at practically all parts of the pathways involved in pain transmission and modulation (the ascending and descending nociceptive pathways), opioid receptors are also present in the brain circuits supporting emotional processing, as well as in neurons which interact with the gastrointestinal tract, the endocrine and autonomic systems, and on cells of the immune system, among others.

There are four major families of endogenous opioids: (beta)-endorphins, enkephalins, dynorphins, and nociceptin/orphanin FQ. These are synthesised within the cell bodies of neurons by breaking down larger molecules and transported to the synapse, where they are released, binding to opioid receptors in the post-synaptic membrane of neighbouring neurons, causing a cascade of intracellular signalling which usually depresses neural activity.

Diagram comparing effects of endogenous opioids - screen-readable version available to download

The classical example of an endogenous opioid is (beta)-endorphin, an MOR agonist which is cleaved from its parent molecule, proopiomelanocortin (POMC). Dynorphin and enkephalin are other endogenous opioids expressed by the dorsal horn. Their expression is increased following peripheral tissue damage, modulating the pain experience. It is also thought that dynorphin release in the dorsal horn is an essential mediator of itch, which is also a bothersome side-effect of exogenous opioids.

The opioid receptors in the EOS are not dormant when not bound by exogenous or endogenous opioids. They have their own constitutive activity, which affects resting pain and emotional experience, and this activity has been shown to be changed by persistent stimulation by exogenous opioids.

Initially, activation of opioid receptors reduces neural transmission quickly. Continued activation over a period of hours to days, however, can lead to an increase in constitutive activity, caused by compensatory changes within the EOS. This can lead to an increase in neural transmission in the presence of opioids. Cessation of opioid therapy at this point will result in a rebound increase in pain, above the baseline of that experienced at initiation of therapy. The mechanism by which this happens is likely to involve other downstream signalling molecules apart from the G proteins mentioned in Step 2.6, as well as changes in receptor expression at the cell surface, and results in the phenomena of opioid tolerance, opioid-induced hyperalgesia and dependence, which we will cover in greater detail later in the week.

We therefore see that the very activation of the MOP receptor in pain pathway neurones which is necessary to provide pain relief is also the key molecular event that initiates the changes within the CNS leading to opioid tolerance and opioid-induced hyperalgesia.

The Endogenous Opioid System and Human Emotions

Apart from playing an important role in the nociceptive pathways that transmit pain signals, activation of the EOS, via its connections with the mesolimbic system, is involved in reward processing and in the experience of positive moods in humans. This plays a key role in the regulation of activities important for survival and homeostasis such as eating and sex, but also in the positive experiences resulting from strenuous social exercise, social bonding, empathy and altruism, among others.

It is therefore perhaps not surprising that the pain relief produced by opioids results not only from the reduced transmission of pain, but also by changing how it is experienced emotionally. In some studies, for example, patients’ descriptions of morphine analgesia reveal that pain intensity remains the same but that the unpleasantness associated with it is reduced. This modulation of the affective experience of pain seems to occur at lower doses than those required to decrease pain transmission.

In addition to this effect on the emotional component of pain, opioid receptor agonism by exogenous opioids can be rewarding in its own right for many people. Many studies have shown opioid-naïve patients experience euphoria or pleasure when administered opioid agonists. This pleasant subjective experience, as well as the many changes in the delicate balance of the EOS on reward and emotional processing, can result in more permanent changes which lead to opioid use disorder. We will explore how this happens in more detail in Step 2.15.


Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and Exogenous Opioids in Pain. Annu Rev Neurosci 2018;41:453-473.

Nummenmaa L, Tuominen L. Opioid system and human emotions. Br J Pharmacol 2018;175(14):2737-2749.

McDonald J, Lambert DG. Opioid receptors. BJA Ed 2015;15:219-224.

Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology 2012;79(8):807-814.

Saanijoki T, Tuominen L, Tuulari JJ, et al. Opioid Release after High-Intensity Interval Training in Healthy Human Subjects. Neuropsychopharmacology. 2018;43(2):246-254.

Herz A. Endogenous opioid systems and alcohol addiction. Psychopharmacol 1997;129(2):99-111.

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