Cell, mouse study finds compound works with fewer side effects than opioids

Fentanyl, Oxycodone, Morphine – these substances are known to many as a source of pain relief and the cause of a painful epidemic of addiction and death.

Scientists have tried for years to balance the potent pain-relieving properties of opioids with their many negative side effects – with mostly mixed results.

The work of John Traynor, Ph.D., and Andrew Alt, Ph.D., and their team at the Edward F. Domino Research Center at the University of Michigan, funded by the National Institute on Drug Abuse, seeks to circumvent these problems. by harnessing the body’s ability to block pain.

All opioids – from poppy-derived opium to heroin – work on receptors naturally found in the brain and elsewhere in the body. One of these receptors, the mu-opioid receptor, binds to natural pain relievers in the body called endorphins and endogenous enkephalins. Drugs that act on the mu-opioid receptor can cause dependence as well as unwanted side effects such as drowsiness, breathing problems, constipation and nausea.

“Normally when you are in pain you release endogenous opioids, but they just aren’t strong enough or long enough,” Traynor says. The team had long speculated that substances called positive allosteric modulators could be used to improve the body’s own endorphins and enkephalins. In a new article published in PNAS, they demonstrate that a positive allosteric modulator known as BMS-986122 can increase the ability of enkephalins to activate the mu-opioid receptor.

Also, unlike opioid drugs, positive allosteric modulators only work in the presence of endorphins or enkephalins, which means they are only involved when needed to relieve pain. They do not bind to the receptor the same way opioids bind in a different place, which improves its ability to respond to pain relieving compounds in the body.

“When you need enkephalins, you release them in a pulsatile fashion in specific areas of the body, and then they are metabolized quickly,” says Traynor. “In contrast, a drug like morphine floods the body and the brain and stays for several hours.”

The team demonstrated the modulator’s ability to stimulate the mu-opioid receptor by isolating the purified receptor and measuring its response to enkephalins. “If you add the positive allosteric modulator, you need a lot less enkephalin to get the response.”

Additional electrophysiology and mouse experiments confirmed that the opioid receptor was more strongly activated by analgesic molecules in the body leading to pain relief. In contrast, the modulator showed greatly reduced side effects of respiratory depression, constipation and addiction.

Their next goal is to measure their ability to enhance endogenous opioid activation under conditions of stress or chronic pain, Traynor explains, to make sure they are effective but do not lead to more dangerous responses like depression. of breathing.

“While these molecules will not solve the opioid crisis,” says Traynor, “they could slow it down and prevent it from happening again, because patients with pain could take this type of drug instead of a traditional opioid.” .

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Material provided by Michigan Medicine – University of Michigan. Original written by Kelly Malcom. Note: Content can be changed for style and length.

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