Structure of Opioid Receptors Paves Way for Addiction Therapies

Opioids remain the most strong and effective pain medications in medicine, but they are also among the most addictive drugs, capable of preventing a person from breathing during an overdose, which can be fatal. Researchers have been rushing to find safer pain reliever medications that target a specific opioid receptor called the kappa opioid receptor, which, unlike other opioid receptors, is exclusively found in the central nervous system. Previous research indicated that such medications may not cause addiction or overdose mortality, but the currently available drugs that target these kappa opioid receptors have their own set of intolerable side effects, including depression and psychosis.

Researchers at the University of Maryland School of Medicine and Washington University have mapped the 3D structure of the central nervous system specific kappa opioid receptor and determined how it differs from the other opioid receptors in one of the first steps toward eventually developing a new wave of kappa opioid receptor drugs without these side effects. They identified what directs the kappa opioid receptor to change its shape, which uniquely binds to opioid medicines, similar to a lock fitting with a certain key in this new study.

Apart from pain relief, opioid receptors are involved in everything from taste and smell detection to digestion and breathing, as well as responding to many of the body’s hormones. Opioid receptors control so many bodily functions by interacting with one of seven cell activity proteins known as G-alpha proteins, which individually assist to specialize the function they suppress in the cell.

“Knowing how these drugs interact with opioid receptors and having a clear view of this molecular snapshot is critical for allowing researchers to develop more effective pain-relieving drugs. This requires a drug that binds to the right type of opioid receptor, such as one in the central nervous system to reduce pain versus the ones that interact in the gut, causing side effects like constipation,” said study corresponding author Jonathan Fay, PhD, Assistant Professor of Biochemistry and Molecular Biology at UMSOM. “Additionally, these next generation medications will need to be designed with the appropriate kind of G-alpha protein in mind, as this will help to precisely target location and cell function by determining the specific shape of the opioid receptor — so the drug only reduces pain without affecting other body functions.”

Because known kappa opioid receptor medicines do not produce the same euphoria as classic opioid medications, they are less likely to be addictive.

The current study employed cryogenic electron microscopy to visualize the structure of the kappa opioid receptor. They had to flash freeze the receptors, which were linked to a hallucinogenic chemical using one of two typical G-alpha proteins. The researchers next employed a separate medication to investigate how the kappa opioid receptor interacted with two other types of G-alpha proteins; one of these G-alpha proteins is exclusively located in the central nervous system, while the other is utilized to detect taste and smell.

The G-protein, according to Dr. Fay, is formed like a chainsaw with a handle and a ripcord. When coupled to the kappa opioid receptor, each G-protein had a slightly different position of its chainsaw handle. This shift in position was crucial in establishing the structure of the kappa opioid receptor and, as a result, which drugs best bind to it. These discoveries may have ramifications for how new medications are designed in the future.

UMSOM Dean Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor, said, “Researchers face an enormous challenge in developing safer pain-reliever drugs since they will need to target both the correct opioid receptor as well as the appropriate G-alpha protein. Studies like these reinforce the mission of our new Kahlert Institute for Addiction Medicine, which aims to help develop this next generation of engineered small molecule drugs that are less addictive.

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