Newly discovered compounds could lead to lower-risk painkillers

Many people with cancer and other chronic health issues depend on painkillers such as morphine and Vicodin to relieve pain.

However, the body's natural tendency to develop tolerance to these medications often requires patients to take higher doses - increasing risks of harmful side effects and dependency.

Now, a new research from the University of Michigan Health System and a major pharmaceutical company has identified a novel approach to moderate and severe pain therapy that paves the way for lower dosage painkillers.

Conventional drug treatments for pain work by targeting the so-called orthosteric site of the opioid receptor that provides pain relief. Targeting this site, however, is a double-edged sword because it is also responsible for all of the drug's unwanted side effects, such as constipation and respiratory depression. Tolerance also limits chronic use of the drugs because higher doses are required to maintain the same effect.

Using cell systems and mouse brain membranes, researchers have identified compounds that bind to a physically distinct and previously unknown "allosteric" site on the opioid receptor- a site that fine-tunes the activity of the receptor.

Not only do these compounds act at a location that hasn't been studied as a drug target before but also they bind to the receptor in a new way to enhance the actions of morphine - which means lower doses can have the same impact.

"The newly-discovered compounds bind to the same receptor as morphine but appear to act at a separate novel site on the receptor and therefore can produce different effects. What's particularly exciting is that these compounds could potentially work with the body's own natural painkillers to manage pain," said co-author John Traynor, Ph.D., professor of pharmacology at the U-M Medical School.

The findings appear in Proceedings of the National Academy of Sciences of the United States of America.