Fentanyl, oxycodone, and morphine are familiar substances to many as pain relievers and are also the cause of a painful epidemic of addiction and death. Scientists have spent years trying to balance the pain-relieving properties of opioids with their many side effects, often with mixed results. Opioid medications act on receptors naturally found in the brain and elsewhere in the body. One of these receptors is the mu-opioid receptor, which binds to the body's natural painkillers called endogenous endorphins and enkephalins. Drugs that act on the mu-opioid receptor can lead to addiction, as well as undesirable side effects such as drowsiness, respiratory issues, constipation, and nausea.
John Trainor from the Edward F. Domino Research Center at the University of Michigan stated, "When a person feels pain, the body naturally releases endogenous opioids, but they are not strong or sustained enough," as reported by Science Daily on the study.
Trainor and his research team hypothesized that materials known as positive allosteric modulators could be used to enhance endorphins and enkephalins in the body. The team highlighted a positive allosteric modulator known as "PMS986122," which can enhance the ability of enkephalin to activate the mu-opioid receptor.
### Natural Pain Relief Mechanism
Unlike opioid drugs, positive allosteric modulators only work in the presence of endorphins or enkephalins, meaning they will only activate when needed to relieve pain. They do not bind to the receptor in the same way as opioids but instead attach to a different site that enhances their ability to respond to the body's pain-relief components. The team demonstrated the positive allosteric modulator's capacity to stimulate the mu-opioid receptor by isolating the pure receptor and measuring how it responds to enkephalin.
