Researchers have spent 40 years trying to find out how the chemical element sodium controls the signaling of opioid receptors in the brain – a class of receptors that play an important role in pain disorders and addictions. Now, scientists from The Scripps Research Institute and the University of North Carolina say they have finally uncovered the mechanism.

The research team, led by Dr. Gustavo Fenalti of The Scripps Research Institute (TSRI), says their findings could lead to the development of new drugs for an array of brain-related medical conditions.

Opioid receptors are naturally triggered by peptide neurotransmitters – endorphins, dynorphins and enkephalins – in the brain.

Synthetic and plant-derived drugs, such as morphine, codeine, oxycodone and heroin, can also activate opioid receptors by mimicking peptide neurotransmitters.

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Researchers say their discovery of how sodium controls opioid receptors in the brain may lead to new treatments for brain-related health conditions, such as mood and pain disorders.

In the early 1970s, researchers from Johns Hopkins University discovered that sodium ions act as a switch for the signaling of opioid receptors, and furthermore, the ions can reduce the interaction between opioid peptides and mimicking drugs, and opioid receptors.

However, it has been unclear as to how sodium ions actually do this.

According to the investigators, opioid receptors have been difficult to study. They note that they are “flimsy and fragile” when created in isolation, meaning they are tricky to analyze using the standard “structure-mapping method” for large proteins – known as X-ray crystallography.

But for this study, findings of which have recently been published in the journal Nature, the team created a new “fusion-protein-stabilized” version of a major opioid receptor in the human brain – the delta opioid receptor.

They formed crystals of the new receptor, and using X-ray crystallography, the researchers were able to view its structure at a resolution of 1.8 angstroms, or 180 trillionths of a meter. The investigators note that this is the clearest picture to date of an opioid receptor.

From this, the researchers discovered that the delta opioid receptor has an “allosteric sodium site,” in which a sodium ion can enter and change receptor activity.

They also detected amino acids that are responsible for triggering the signal-modulating activity of the sodium ions and keeping the ions in place.

“We found that the presence of the sodium ion holds the receptor protein in a shape that gives it a different affinity for its corresponding neurotransmitter peptides,” explains Dr. Fenalti.

Commenting on their findings, Prof. Raymond Stevens, of TSRI and senior author of the study, says:

This discovery has helped us decipher a 40-year-old mystery about sodium’s control of opioid receptors. It is amazing how sodium sits right in the middle of the receptor as a co-factor or allosteric modulator.”

The investigators then created new adaptations of the delta opioid receptor by mutating amino acids in the main sodium sites.

From this, the investigators found that changes in specific amino acids trigger major adjustments in the normal signaling response of the delta opioid receptor.

The researchers say these findings mean there may be many ways in which drugs could target not only delta opioid receptors, but also the other two opioid receptors in the brain, called mu and kappa.

“The sodium site architecture and the way it works seems essentially the same for all three of these opioid receptor types,” says Dr. Fenalti.

Overall, the team says their research could lead to new treatment options for medical conditions related to the brain.

“It opens the door to understanding opioid related drugs for treating pain and mood disorders, among others,” Dr. Fenalti adds.

In other news related to brain health, Medical News Today recently reported on a study suggesting that brain training boosts mental skills of older adults, while another study suggests caffeine may boost long-term memory.