Endogenous versus Medical Opioid Actions

Study upends conventional view of opioid mechanism of action | National Institutes of Health (NIH) – May 10, 2018

NIH-funded scientists find new molecular target for developing safer pain medications.

A new discovery shows that opioids used to treat pain, such as morphine and oxycodone, produce their effects by binding to receptors inside neurons, contrary to conventional wisdom that they acted only on the same surface receptors as endogenous opioids, which are produced naturally in the brain.  

However, when researchers funded by the National Institute on Drug Abuse (NIDA) used a novel molecular probe to test that common assumption, they discovered that medically used opioids also bind to receptors that are not a target for the naturally occurring opioids.

This difference between how medically used and naturally made opioids interact with nerve cells may help guide the design of pain relievers that do not produce addiction or other adverse effects produced by morphine and other opioid medicines

Naturally occurring opioids and medically used opioids alike bind to the mu-opioid receptor, a member of a widespread family of proteins known as G protein-coupled receptors (GPCRs).

Recent advances in understanding the three-dimensional structure of GPCRs have enabled researchers to create a new type of antibody biosensor, called a nanobody, that generates a fluorescent signal when a GPCR is activated. This enables scientists to track chemicals as they move through cells and respond to stimuli.

Using this nanobody, the researchers first showed that when a naturally occurring opioid binds to and activates the mu-receptor on the surface of a neuron, receptor molecules enter the cell inside what is known as an endosome.

There, the mu-receptor remains activated over a period of several minutes, which itself was a new discovery, since it was believed that the opioid receptor is only activated on the surface of nerve cells. Proteins that interact with receptors on the cell surface control all sorts of biological processes and provide targets for therapeutic intervention.

With opioid medications, however, the researchers made two additional discoveries.

  1. First, there are large differences across a range of clinically relevant opioid drugs in how strongly they induce receptor activation in endosomes.
  2. Second, the opioid drugs uniquely induce rapid nanobody signaling, within tens of seconds, in an internal cellular structure known as the Golgi apparatus in the main body of the neuron.

Further investigation showed that therapeutic opioids also uniquely activate mu-opioid receptors in related structures, known as Golgi outposts, in the long, branched structures of neurons.

Based on these findings, the researchers hypothesize that current medically used opioids distort the normal time and spatial sequence of mu-opioid receptor activation and signaling.

This distortion may provide the mechanistic link that explains the undesired side effects of opioid medicines suggests new avenues for designing agents that do not produce addiction or other adverse effects associated with these drugs.

Or, it may not.

It looks to me like they are jumping on a slim possibility and making it look like it will be a breakthrough.

There’s no evidence whatsoever that the difference between endogenous opioids and therapeutic opioids will be that only the medical opioids are addictive.

This new biosensor opens our eyes to a previously unknown level of diversity and specificity in the cellular actions of opioids,” said Dr. Miriam Stoeber, the study’s first author. Dr. Mark von Zastrow, senior author of the study, added, “We were surprised to see that drugs such as morphine activate opioid receptors in a location at which naturally occurring opioids do not.”

The article adds the following general wishy-washy vague disclaimer at the end. In my opinion, this disclaimer should be placed prominently at the very beginning of an article like this, one that speculates so widely.

This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.


4 thoughts on “Endogenous versus Medical Opioid Actions

  1. Laura P. Schulman, MD, MA

    I don’t think it’s wishy-washy. I think it’s an accurate description. This finding that exogenous opiates bind to the Golgi apparatus while endogenous opiates do not, is a fascinating outcome that opens the door to further research that might explain why it is that we need pain medication at all. A big question is: since we have endogenous opiates (the endorphin system), why doesn’t that take care of things for us? What’s different about exogenous morphine, for instance? Why does it work when our built-in pain control system gets overwhelmed? This finding that exogenous opiates get sucked into the cytoplasm and into the Golgi bodies is fascinating. I’m looking forward to seeing what future research discovers.

    Liked by 1 person

    1. Zyp Czyk Post author

      I don’t understand how they can assume that this difference between the molecules will be exactly what they want: that only the exogenous opioids are addictive.

      These molecules could differ in an infinite number of ways, couldn’t they?


  2. Robert Schubring

    What’s typical of this report, is that after the facts have been selectively screened and twisted by Dr Nora Volkow and others to fit a political agenda, the press release bears little resemblance to the scientific paper that prompted the press release. What the scientific paper discusses is a mechanism by which the human body stockpiles morphine for future use, by linking it with peptide bonds to groups of amino acids and fats. And what the press release breathlessly tries to conceal, is the fact that plain old ordinary morphine that gets made in our own cells, goes naturally roaming around in those cells, where it can encounter Golgi bodies that turn it into morphine peptides for storage, mitochondria where it works to regulate oxygen metabolism, and nerve receptors where it regulates nociception and sleep. Using the magical term “endorphin”, which has been obsolete since 1987, it is pretended that poppy-derived morphine is somehow magically distinct from human-derived morphine, even thought the two sources of substance are chemically indistinguishable once they enter the body.

    Dr Volkow needs to get a grip on the political realities, which are that it is as impossible to continue pretending that “endorphins” are different from poppy-derived morphine, as it is to pretend that the Earth is flat. If her agency is to continue to have relevance to global medical research, it needs to stop pretending that century-old false theories invented by racists to justify attacks on certain groups of people, ever had any truth to them. The Drug War that the racist Eugenics theories spawned, has been a total disaster for all of humanity, and must immediately be halted.

    Once one recognizes that morphine serves necessary functions in the human body, and that even Hillary Clinton and Jeff Sessions have it in them, despite their protestations to the contrary, one must address the opioid cravings that certain individuals have, as either a form of dietary deficiency for which their bodies are attempting to compensate, or some sort of sensory failure that’s causing them not to notice when they’ve consumed enough of the substance already.

    Obesity may provide a useful model for the future of addiction studies. The obese person eats far more food than necessary and stores much of it as fat. Either the obese person does not feel fed because of a defect in how he senses satisfaction, or else the obese person’s diet is lacking in some necessary nutrient and the person is attempting to obtain that missing nutrient by gorging on whatever nutrients can be found. Either way, fixing the problem requires constructive engagement with the obese patient, to learn more details about their food cravings and what triggers them. Commanding the person to suffer because of their illness, is unhelpful.

    Liked by 1 person

    1. Zyp Czyk Post author

      I’ve tried to point out the equivalence of opioid “drugs” and our endogenous opioids in this blog too:

      My theory is that pain “uses up” our endorphins, which we must then supplement with exogenous opioids.

      This would also explain why those with pain don’t get euphoria:



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