Studies Reveal Why Some Painkillers Lose Their Effectiveness

Studies Reveal Why Some Painkillers Lose Their Effectiveness

Image courtesy of University of Colorado

Canadian researchers have identified how neural cells are able to build up resistance to opioid painkillers. Opioid-based drugs, such as morphine and codeine, have been used for centuries to treat pain – but until now little has been known about how they lose their effectiveness in the hours, days and weeks following the first dose.

“Our study revealed cellular and molecular mechanisms within our bodies that enables us to develop resistance to this medication, or what scientists call drug tolerance,” said lead researcher Graciela Pineyro, MD, PhD, of the Departments of Psychiatry and Pharmacology at the University of Montreal and the Sainte-Justine Hospital Research Center. “A better understanding of these mechanisms will enable us to design drugs that avoid tolerance and produce longer therapeutic responses.”

The research team looked at how opioids interact with molecules called “receptors” that exist in every cell in the human body. Receptors receive “signals” from chemicals they come into contact with, and the signals cause the cells to react in different ways. Once activated by a drug, receptors move from the surface of the cell to its interior – where they are either destroyed or return to the surface to be used again in a process known as “receptor recycling.” Researchers found that some of the recycled receptors have less tolerance to analgesics.

“We now know that drugs that activate the same receptor do not always produce the same kind of effects in the body, as receptors do not always recognize drugs in the same way,” Pineyro explained. “Receptors will configure different drugs into specific signals that will have different effects on the body.”

Pineyro is attempting to tease the painkilling function of opioids from the part that enables tolerance to build up. “If we can understand the chemical mechanisms by which drugs produce therapeutic and undesired side effects, we will be able to design better drugs,” Pineyro said.

The research, which was funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health, is being published in the Journal of Neuroscience.

In a second study of how cell receptors react to an opioid, researchers at the University of Colorado Boulder discovered that two protein receptors in the central nervous system team up to respond to morphine and cause unwanted neuroinflammation.

“The exciting thing about this research is that we have discovered that there is not just one receptor that detects morphine, there is a second one that nobody knew about before,” said Linda Watkins, a distinguished professor in CU-Boulder’s psychology department. “We have shown this protein complex essentially cuts morphine off at the knees, preventing it from doing its job in controlling pain.”

It is estimated that 116 million Americans have chronic pain, costing the nation as much as $635 billion annually in lost productivity and health care expenses. The U.S. is one of the world’s highest users of morphine, which was first marketed as a cure for opium and alcohol addiction.

“While inflammation is part of the body’s natural defense system to protect it after injury or infection, too much inflammation is unhealthy,” said Hang Yin, assistant professor in the chemistry and biochemistry department at CU-Boulder. “We hope our new findings on how this particular protein complex works can help us to understand morphine-induced inflammation and eventually lead to therapeutics to make morphine work more efficiently with fewer side effects.”

The research, which was funded by the National Institutes of Health, is being published the Proceedings of the National Academy of Sciences.

Authored by: Pat Anson, Editor