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The United States is in the midst of a public health crisis when it comes opioid drug use. As physicians and public health officials struggle to keep up with the current rash of addiction diagnoses and overdose deaths (See “Synthetic Opioid Driving Overdose Death Rate”), there is still no clear explanation why this particular type of drug is so prone to abuse. A new study from the University of California San Francisco (UCSF) suggests that synthetic opioid substances like hydrocodone and fentanyl affect neurons in a much different manner than opioids naturally produced by the brain; those effects may offer new insights into how to best fight the opioid epidemic in the future.
One of these is not like the other?
In her acclaimed essay, “Heroin/e,” Cheryl Strayed wrote about her addiction to heroin. In the piece, she described the drug in this way: “I loved it. It was the first thing that worked. It took away every scrap of hurt that I had inside of me. When I think of heroin now, it is like remembering a person I met and loved intensely.”
While many high-profile athletes have spoken fondly of the “runner’s high,” or release of naturally produced endorphins after strenuous exercise, they don’t tend to describe it as a love affair. Yet, even though people report such differences in sensation between endogenous (the body’s own) and exogenous (external drug) opioids, Rita Valentino, director of the division of neuroscience and behavior branch at the National Institute of Drug Abuse (NIDA) says scientists believed that both types of compounds worked on neurons in similar ways.
“We thought the first step of either the drug or the endogenous opioid producing an effect was its interaction with receptors on the cell membrane,” she explains. “Both bind to this receptor protein on the cell, initiating the same cascade of signaling to produce pain relief or other effects, and we thought that things sort of stopped right there.”
But Miriam Stoeber, a post-doctoral fellow in Mark von Zastrow’s lab at UCSF, says such common wisdom didn’t square with the experiences people have with opioid drugs—starting with the reports of intensely pleasurable and rewarding effects following use.
“We’ve known for a long time that drugs can produce these pathological conditions of addiction, tolerance, and overdose,” she says. “You don’t have those same kinds of behaviors involved with any sort of natural reward chemical. It seems clear that there is something that drugs are doing that endogenous peptides like endorphins are not doing. But it wasn’t clear what—especially since we thought both acted the same way on the opioid receptors on the cell’s surface.”
Beyond the plasma membrane
To see if the two types of opioids really were initiating the same cascade of signaling effects within living striatal neurons, von Zastrow, a professor of psychiatry at UCSF, Stoeber, and colleagues used a specially designed biosensor to follow what both endogenous and exogenous opioids were doing inside in the cells. When an opioid, natural or not, binds with an opioid receptor, the biosensor turns on; then the researchers can follow the downstream effects using specialized microscopy techniques. Using this method, the researchers discovered that opioids not only activated receptors on the surface of brain cells but also inside the membrane — in specialized organelles called endosomes. Furthermore, synthetic drugs were also able to activate receptors in another organelle, called the Golgi apparatus—a place where natural opioids did not activate receptor pools at all. The results were published in the May 5 issue of Neuron.
“Using this kind of sensor tool, we were able to see that there were very interesting differences in receptor activation and the location of that activation between endogenous and exogenous opioids,” he says. “In some ways, it makes sense. These different compounds have chemistries that really are quite different from one another. In principle, you’d expect there would be differences in the way they would interact with receptors, not to mention functional consequences from those differences, too.”
Valentino says these findings challenge the current dogma that neural signaling is only activated by receptors at the plasma membrane.
“We see now that the receptor can be activated in different subcellular compartments, dependent on whether they are activated by an endogenous opioid or an opioid drug. With these drugs, they are activating receptors in the Golgi, which helps ship out proteins to other parts of the cell,” she says. “This implies there is an entirely new level of receptor signaling going on. And if signaling in these different compartments translates to different functional effects—perhaps different side effects, advantageous effects, or clinically relevant effects for these drugs—we can use this information to better design drugs that offer pain relief without the adverse effects like respiratory depression or addiction.”
Von Zastrow says he is not sure what the functional significance of the activation of receptor pools in the Golgi apparatus might be, but it’s something that he and his colleagues are actively studying. They also hope to follow this study by looking at the specific activation patterns of different opioid drugs on neurons.
“We’re trying to figure out the downstream consequences of this activation of receptors in the Golgi apparatus, for one, so we can see how it might affect signaling,” he says. “But we are also interested in another big question: how these different drugs may be affecting signaling differently. Certainly, some fraction of the heterogeneity of effects and the abuse responses may be explained by what pools of receptors a certain drug is interacting with. It’s something we need to look into.”
But, even as he discusses all the important work that is still yet to be done, von Zastrow says these findings generate a “great deal of excitement” regarding developing new analgesic drugs that are safer and more effective, as well as other therapeutic drugs that might help treat addiction and reverse overdose.
“Our study provides support for the idea that there may be more control and potential for therapeutic benefit that could be achieved by exploring these very basic aspects of how receptors get activated by these drugs,” he says. “It has the capacity to open an entirely new horizon into therapeutic development in the future, not only for pain relief but also for addiction.”