Chemists ID possible analgesic without dependence

According to the National Institute for Combating Drug Abuse, about 1.7 million Americans suffer from addiction related disorders related to opioid use. This represents an economic burden of over $ 78 billion a year in health care costs and substance abuse treatment, as well as the loss of worker productivity and the increase in criminal activity. In 2017, more than 47,000 people died as a result of opioid abuse and related drugs.

As the problem worsens, researchers are looking for non-addictive chronic pain treatment options that produce little or no side effects.

Ken Hsu, professor of chemistry at the University of Virginia, and his graduate student, Myungsun Shin, have identified an enzyme that "gnaws the fat molecules" to produce chemical signals that control inflammation.

The natural enzyme, called diacylglycerol lipase-beta, or DAGL-beta, is a potential new drug target to reduce pain. During his postdoctoral training, Hsu has developed selective molecules that inhibit DAGL-beta and reduce inflammation, in the same way as aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDs. . However, unlike NSAIDs, DAGL-beta inhibitors can relieve pain without gastrointestinal toxicity in preclinical models when used over the long term. And unlike opioids, DAGL-beta inhibitors do not exhibit addictive properties.

"This could be a new way to treat inflammation and long-term pain without the side effects of toxicity and dependence risk seen with current treatment options," Hsu said. "Generally, if we block inflammation, we also affect the immune response, but we suggest a different approach, an approach to stopping inflammation without affecting the normal immune response."

The results of Hsu have been published today in the online edition of the newspaper Cellular chemical biology.

According to Hsu, studies conducted by UVA in collaboration with Virginia Commonwealth University demonstrate that DAGL-beta inhibitors are extremely effective at reducing various pain conditions, including neuropathic pain and peripheral neuropathy induced by chemotherapy.

In this new study, the Hsu laboratory has discovered a new role for DAGL-beta in dendritic cells, a specialized type of innate immune cells that not only control inflammation, but can also activate our body's ability to fight infections by stimulating T cells, which produce an immune response.

"We found that by blocking DAGL-beta, we could stop the inflammation without affecting immunity," Hsu said. "This supports the idea that DAGL-beta is a viable target for long-term blockade of inflammation and pain without potentially compromising our immune system."

Hsu's research program focuses on the use of chemistry to find new ways to modulate the immune system, whether it is to fight cancer or, in this case, to better understand the molecular pathways that can be targeted to reduce chronic inflammation and pain.