Opioid Drugs Work Differently Than Natural Opioids

A new study offers a reason why opioid drugs have more powerful effects than the body’s own morphine-like chemicals. The research could influence future pain drug development efforts. Image credit: eraxion/123RF Stock Photo.

Opioid drugs like morphine and fentanyl relieve pain by attaching to and activating opioid receptors, which are proteins on the surface of nerve cells. The body’s own morphine-like chemicals, called endogenous opioids, do the same.

As a result, scientists thought opioid drugs and endogenous opioids worked in the same way to ease pain. Now, a recent study questions this conventional wisdom.

Researchers led by Mark von Zastrow, in collaboration with Aashish Manglik, both at the University of California, San Francisco, show that opioid drugs and natural opioids first activate opioid receptors at the cell membrane (which separates the inside of cells from the outside environment), and then in structures within the cell called endosomes.

But only opioid drugs go a step further: they also activate the receptors in the Golgi apparatus, a structure deeper inside the cell.

This difference could explain why opioid drugs have such potent effects, often leading to addiction.

The paper is a “real eye-opener,” with great implications for future development of pain-relieving drugs, says William Schmidt, head of NorthStar Consulting in Davis, California, which provides advice to companies working on new pain medications. Schmidt was not involved in the current study.

“This offers a new way of thinking about how [natural opioids] may interact with cells versus [opioid] drugs, finally allowing us to better understand the similarities and differences we see between them,” he said.

The study was published online May 10 in the journal Neuron.

A new tool leads to a surprising discovery
In their study, the researchers used a so-called nanobody biosensor. This tool consists of part of an antibody (a type of protein) fused to a fluorescent protein.

The biosensor detects changes to the structure of the opioid receptor that occur when an opioid drug or natural opioid attaches to the receptor. The fluorescent protein allows researchers to see activation of the receptor at the cell membrane.

The researchers also used a special microscope that allowed them to follow the path the opioid receptors take inside the cell after becoming activated at the cell membrane.

The team already knew that after opioid drugs or natural opioids attach to opioid receptors at the cell membrane, the receptors are engulfed into specialized structures called endosomes. This process, called endocytosis, controls the number of receptors in the cell.

Investigators had long believed that the receptors, once taken up by the endosomes, would no longer remain active there. But the biosensor revealed that the receptors were in fact still active within these structures.

Even more surprising, the researchers discovered that opioid drugs like morphine, but not natural opioids, penetrated even deeper inside the cell. In this case, the drugs activated opioid receptors in the Golgi apparatus. This is a structure that packages and processes proteins so that they are delivered to the right places inside or outside of the cell.

“This clearly shows a striking difference in where these different compounds [opioid drugs vs. natural opioids] will activate these receptors, and that influences [cell] signaling,” says Manglik. Here, cell signaling refers to communication events, involving various molecules, that take place inside cells after opioids attach to their receptors. These events ultimately result in a drug effect, such as pain relief.

“The opioid drugs are getting into the cell and activating opioid receptors in places where endogenous opioids aren’t activating receptors at all—and it’s not something we ever would have anticipated,” Manglik said.

What does it all mean?
Von Zastrow believes that this difference in where opioid receptors become activated in the cell may explain why opioid drugs produce such pleasurable and rewarding effects, increasing the risk of addiction.

“One could speculate that the pathological effects of these drugs, including their addictive properties, could be a consequence of those activations” in the Golgi apparatus, deep inside the cell, he said.

Schmidt says the findings offer new insight on why current opioid drugs can have such detrimental side effects, how to improve those drugs, and how to better develop new, safer pain medications.

“This is entirely new, and it’s an idea that could drive new drug development,” he said.

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Kayt Sukel is a freelance writer based outside Houston, Texas.