The study shows how paracetamol can actually relieve pain

The study shows how paracetamol can actually relieve pain

A new study from Indiana University scientists could help the pharmaceutical industry better understand a popular over-the-counter painkiller: Tylenol.

Michaela Dvorakova, a postdoctoral researcher at IU's Gill Institute for Neuroscience and the College of Arts and Sciences' Department of Psychological and Brain Sciences, and Gill Institute research scientist Alex Straiker, published the study inCell Reports Medicine. Their discovery, which describes a previously unknown way in which the drugs target pain, could change the way pharmacologists think about treating pain and design safer and more effective painkillers.

The researchers found that acetaminophen inhibits an enzyme that produces one of the endogenous cannabinoids, 2-arachidonoyl-glycerol or 2-Ag-endocannabinoids, produced by the body to activate CB1 receptors, the same receptor that produces the psychoactive effects of cannabis.

Although acetaminophen, also known as Tylenol or acetaminophen, is the most common pain and fever medication in the United States, how it relieves pain is still a mystery.

There are hypotheses, but we still don't know exactly how it works. Previously we thought that increased endocannabinoids in our bodies meant less pain, but our study shows that in the case of 2-Ag it could be the opposite. In fact, reduced levels of 2-Ag lead to reduced pain. “

Michaela Dvorakova, a postdoctoral researcher at IU's Gill Institute for Neuroscience

In high doses, acetamol can be toxic to the liver. Acetaminophen toxicity results in 500 deaths per year in the United States and is the second leading cause of liver transplantation worldwide. Because of its wide availability and its combination in other products, more than 60 million Americans consume acetaminophen weekly, making it critical to understand how it targets pain receptors.

“If you don’t know what the goal is, you can’t design an alternative,” Straiker said. "Our research suggests that this enzyme could be the target. In this case, you can start developing drugs that target this specific enzyme, but without this toxicity."

There has been skepticism in the research community about a new mechanism of action for acetaminophen, Straiker said. When 50 years of research showed that activating CB1 receptors in the body produced pain relief, scientists settled on this concept.

“It can be difficult to break through that dogma,” Straiker said.

In the future, the research team is looking into evaluating other common painkillers, such as ibuprofen and aspirin, to see if they have similar mechanisms of action.

Additional authors of the study include Ken Mackie of IU's Gill Institute, as well as Taryn Bosquez-Berger, Jenna Billingsley, Natalia Murataeva, Taylor Woodward, Emma Leishman, Anaëlle Zimmowitch, Anne Gibson, Jim Wagermiller and Heide-Bradshaw. Ruyi Cai, Shangxuan Cai and Yulong Li from Peking University School of Life Sciences; Tim Ware of Scripps Research Institute; and Ku-Lung Hsu from the University of Texas at Austin.

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