Body's 'natural opioids' affect brain cells much differently than morphine

May 10, 2018, University of California, San Francisco
Fluorescence micrograph of a neuronal cell body showing the location of opioid receptor activation detected by the new biosensor immediately before (top panel) and 20 seconds after (bottom panel) application of morphine. Credit: Drs. Miriam Stoeber and Damien Jullié

A new study led by UC San Francisco scientists shows that brain cells, or neurons, react differently to opioid substances created inside the body - the endorphins responsible for the "natural high" that can be produced by exercise, for example - than they do to morphine and heroin, or to purely synthetic opioid drugs, such as fentanyl. The researchers say their findings may help explain why the use of synthetic opioids can lead to addiction.

Since both synthetic opioids and the natural, "endogenous" opioids produced in the brain bind to and activate receptors on the surface of nerve , scientists have long assumed that both types of molecules target the same cellular systems. But the new research reveals that these molecules also activate opioid receptors inside cells, and that the locations of these activated intracellular receptors differ between natural and synthetic opioids.

In the new study, published in the May 10, 2018 issue of Neuron, the researchers report that this difference could help explain why the effects of synthetic are more rewarding than those produced by .

"There has been no evidence so far that opioid drugs do anything other than what natural opioids do, so it's been hard to reconcile the experiences that drug users describe—that opioid drugs are more intensely pleasurable than any naturally rewarding experience that they've ever had," said Mark von Zastrow, MD, Ph.D., a professor of psychiatry at UCSF and senior author on the new paper. "The possibility that these opioid drugs cause effects that natural opioids cannot is very intriguing because it seems to parallel this extremely rewarding effect that users describe."

Researchers in von Zastrow's lab collaborated with Aashish Manglik, MD, Ph.D., assistant professor of pharmaceutical chemistry, to create a "biosensor" that binds to the along with an opioid drug or natural opioid. The tool allowed the scientists to see what's happening inside cells, giving them a closer look than ever before at opioids' effects. "It's a way of sniffing out where these receptors are active in the particular types of neurons in which opioids work," explained von Zastrow, a member of the UCSF Weill Institute for Neurosciences.

It has generally been thought that all opioid molecules, natural or synthetic, impart their signal only from receptors on the surface of the cell. Opioid-bound receptors are then taken inside the cell to compartments called endosomes, but receptors were thought not to signal from this location. Overturning this long-held view, the research team discovered that receptors actually remain active in endosomes and they use the endosome to sustain the signal within cells.

But in the most intriguing twist, the research team discovered that morphine and synthetic opioids activate receptors in yet another internal location called the Golgi apparatus, where endogenous opioids are unable to produce any activation at all.

"It really surprised us that there was a separate location of activation for drugs in the Golgi apparatus that could not be accessed by endogenous opioids," said first author Miriam Stoeber, Ph.D., a postdoctoral researcher in von Zastrow's lab. "Drugs, which we generally thought of as mimics of endogenous opioids, actually produce different effects by activating receptors in a place that natural molecules cannot access."

Moreover, morphine and synthetic opioids crossed cell membranes without binding or entering endosomes. They traveled directly to the Golgi apparatus, reaching their target much more quickly than endogenous opioids got into endosomes, taking only 20 seconds compared to over a minute. This time difference could be important in the development of addiction, the researchers said, because typically the faster a drug takes effect, the higher its addictive potential.

The scientists hope to apply their findings to create new types of opioid-based pain medications that have a lower risk for addiction. They also plan to screen other existing medications to see if they act more like natural or synthetic opioids.

"We're very excited about the possibility of leveraging these principles to develop better or more selective drugs that have the ability to get into the brain, but then differ in their activities at internal locations within individual neurons," says von Zastrow. "This is an area that hasn't been explored in development because people haven't been thinking about it, but the potential is there."

Explore further: Opioids produce analgesia via immune cells

More information: Miriam Stoeber et al. A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action, Neuron (2018). DOI: 10.1016/j.neuron.2018.04.021 , www.cell.com/neuron/fulltext/S0896-6273(18)30329-5

Related Stories

Opioids produce analgesia via immune cells

January 17, 2017
Opioids are the most powerful painkillers. Researchers at the Charité - Universitätsmedizin Berlin have now found that the analgesic effects of opioids are not exclusively mediated by opioid receptors in the brain, but ...

Alternative, non-opioid treatments for chronic pain

March 30, 2018
An estimated 2 million people in the U.S. are addicted to prescription opioids—powerful doctor-prescribed medications for chronic or severe pain. The drugs are commonly prescribed to treat gastrointestinal pain caused by ...

Researchers identify brain mechanism linking PTSD and opioid addiction

April 23, 2018
Researchers at Western University have shown that the recall of traumatic memories enhances the rewarding effects of morphine, shedding light on the neurobiological link between post-traumatic stress disorder (PTSD) and opioid ...

Researchers examine how opioids affect proteins in the brain other than opioid receptors

December 6, 2017
In a new study, researchers have characterized the effects of a series of opioids on proteins in the brain other than opioid receptors. In the British Journal of Pharmacology study, several synthetic opioids inhibited serotonin ...

Researchers see promise for safer opioid pain reliever

April 23, 2018
Researchers at the University of Michigan have engineered a new compound that animal tests suggest could offer the pain-relieving properties of opioids such as morphine and oxycodone without the risk of addiction. With more ...

This engineered painkiller works like an opioid but isn't addictive in animal tests

April 27, 2018
Sometimes forgotten in the spiraling U.S. crisis of opiate abuse is a clinical fact about narcotic pain medications: addiction is basically an unwanted side effect of drugs that are highly effective at blunting pain.

Recommended for you

Sensitive babies become altruistic toddlers

September 25, 2018
Our responsiveness to seeing others in distress accounts for variability in helping behavior from early in development, according to a study published September 25 in the open-access journal PLOS Biology by Tobias Grossmann ...

Immune cell pruning of dopamine receptors may modulate behavioral changes in adolescence

September 25, 2018
A study by MassGeneral Hospital for Children (MGHfC) researchers finds that the immune cells of the brain called microglia play a crucial role in brain development during adolescence, but that role is different in males and ...

Scientists reverse a sensory impairment in mice with autism

September 25, 2018
Using a genetic technique that allows certain neurons in the brain to be switched on or off, UCLA scientists reversed a sensory impairment in mice with symptoms of autism, enabling them to learn a sensory task as quickly ...

Why it doesn't get dark when you blink

September 25, 2018
People blink every five seconds. During this brief moment, no light falls on the retina, yet people continue to observe a stable picture of the environment with no intervals of darkness. Caspar Schwiedrzik and Sandrin Sudmann, ...

Researchers identify new cause of brain bleeds

September 25, 2018
A team of researchers including UCI project scientist Rachita Sumbria, Ph.D. and UCI neurologist Mark J. Fisher, MD have provided, for the first time, evidence that blood deposits in the brain may not require a blood vessel ...

Lung inflammation from childhood asthma linked with later anxiety

September 25, 2018
Persistent lung inflammation may be one possible explanation for why having asthma during childhood increases your risk for developing anxiety later in life, according to Penn State researchers.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

joel in oakland
not rated yet May 11, 2018
"...scientists have long assumed.."
It'd be wonderful (but maybe career suicide) if someone studied how this - and similar incorrect - assumption/s came to be, given that it's seriously wrong. Maybe the tools to probe were only recently available. Even so, when researchers' assumption conflict with user reports that ought to call assumptions into question.

"The possibility that these opioid drugs cause effects that natural opioids cannot is very intriguing because it seems to parallel this extremely rewarding effect that users describe."

Wouldn't you think.

But maybe I'm making too much of this article's wording. I hope so.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.