August 11, 2022

Chemist IDs Possible Addiction-Free Painkiller

According to the National Institute on Drug Abuse, approximately 1.7 million Americans suffer from substance abuse disorders related to the use of opioids for pain relief. This results in an economic burden of more than $78 billion a year in health care and addiction treatment costs, as well as lost worker productivity and increased criminal activity. In 2017, more than 47,000 people died from drug abuse involving opioids and related drugs.

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

University of Virginia chemistry professor Ken Hsu and his graduate student, Myungsun Shin, have identified an enzyme that “chews up fat molecules” to produce chemical signals that control inflammation.

The natural enzyme, called diacylglycerol lipase-beta, or DAGLb, is a possible new drug target for reducing pain. Hsu developed, during his postdoctoral training, selective molecules that inhibit DAGLb and reduce inflammation, similar to aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDs. However, unlike NSAIDs, DAGLb inhibitors can provide pain relief without gastrointestinal toxicity in preclinical models when used long term. And unlike opioids, DAGLb inhibitors do not exhibit addictive properties.

“This could be a new avenue for treating long-term inflammation and pain without the side effects of toxicity and risk of addiction seen with current treatment options,” Hsu said. “Generally, if we block inflammation, we also affect the immune response. But we offer a different approach, one where we can stop inflammation without affecting the normal immune response.

by Hsu results were published today in the online edition of the journal Cell Chemical Biology.

According to Hsu, studies conducted at UVA in conjunction with Virginia Commonwealth University demonstrate that DAGLb inhibitors are highly effective in reducing different pain states, including neuropathic pain and chemotherapy-induced peripheral neuropathy.

In the new study, the Hsu lab discovered a new role for DAGLb in dendritic cells, a specialized type of innate immune cell that not only controls inflammation but can also activate our body’s ability to fight infection by stimulating T cells, which produce an immune system. responnse.

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

Hsu’s research program is focused on using chemistry to find new ways to modulate the immune system, whether to fight cancer or, in this case, a better understanding of molecular pathways that can be targeted. to reduce chronic inflammation and pain.

Graduate student Shin conducted the lab experiments for this study in collaboration with UVA pathology professor Timothy Bullock. The project is supported by the National Institute of Drug Abuse and the National Cancer Institute.