Body’s ‘Natural Opioids’ Affect Brain Cells Much Differently Than Morphine

Source: University of California, San Francisco

Summary: A new study 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.

Since both synthetic opioids and the natural, “endogenous” opioids produced in the brain bind to and activate opioid receptors on the surface of nerve cells, 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. Researchers from the University of California report that this difference could help explain why the effects of synthetic opioid drugs are more rewarding than those produced by endogenous opioids. The study findings were published in the journal Neuron.

Nerve cell body

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

The research team created a “biosensor” that binds to the opioid receptors along with an opioid drug or natural opioid. The tool allowed them 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. 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 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. The researchers say their findings may help explain why the use of synthetic opioids can lead to addiction.

Prof. Mark von Zastrow said, “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.”

More Information: Miriam Stoeber et al, “A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action”, Neuron (2018).

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