Opioid drugs and natural (or endogenous) opioids run along different paths inside neurons, which could explain why the “runner’s high” that results from exercise differs from the unnatural high produced by morphine, heroin, or synthetic opioids. Whereas opioid drugs and natural opioids both activate opioid receptors on the surface of neurons, opioid drugs take a detour after neurons internalize them.

By tracking the path taken by opioid drugs, researchers based at the University of California, San Francisco (UCSF), hope to better understand opioid addiction. The researchers, led by Mark von Zastrow, M.D., Ph.D., a professor of psychiatry at UCSF, also hope that their findings will lead to less addictive pain-killing drug designs.

“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 Dr. von Zastrow. “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.”

Dr. von Zastrow and colleagues essentially found a way to track opioid drugs and endogenous opioids, and what they discovered came as a surprise. Opioid drugs achieve opioid receptor activation in the Golgi apparatus. Endogenous opioids do not.

Details appeared May 10 in the journal Neuron, in an article entitled “A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action.” The article describes how the UCSF team created a biosensor that binds to opioid receptors along with opioid drugs or natural opioids. With their biosensor, the UCSF scientists uncovered a “real-time map of the spatiotemporal organization of opioid receptor activation in living neurons.”

“Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization,” wrote the article’s authors. “Drugs produce a different activation pattern by additionally driving opioid receptor activation in the somatic Golgi apparatus and Golgi elements extending throughout the dendritic arbor.”

Differences in the activation patterns of opioid drugs and endogenous opioids could help explain why the effects of opioid drugs are more rewarding than those produced by endogenous opioids. Now that these differences are being uncovered, old assumptions about opioid signaling may need to be revised.

It had 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 UCSF team discovered that receptors remain active in endosomes and they use the endosome to sustain the signal within cells. Even more intriguingly, the UCSF team discovered that morphine and synthetic opioids activate receptors in yet another internal location, the Golgi apparatus, where endogenous opioids are unable to produce any activation at all.

Moreover, morphine and synthetic opioids crossed cell membranes without binding receptors 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,” said Dr. von Zastrow, who is the senior author of the Neuron article. “This is an area that hasn't been explored in drug development because people haven't been thinking about it, but the potential is there.”

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