An Addiction-Free, Long-Term Pain Reliever

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

As the problem amplifies, researchers are seeking non-addictive chronic pain treatment options that produce no, or at least few, negative side effects. A study published online today in Cell Chemical Biology identifies an enzyme that ‘chews up’ fat molecules to produce chemical signals that control inflammation.

This naturally occurring enzyme, DAGLβ, is a possible new drug target for reducing pain. During his postdoc training, senior author Ku-Lung Hsu of UVA developed selective molecules that inhibit DAGLβ and reduce inflammation, similar to aspirin and other NSAIDS. However, unlike NSAIDs, DAGLβ inhibitors can provide pain relief without gastrointestinal toxicity in preclinical models when used long term. And unlike opioids, DAGLβ inhibitors do not exhibit addictive properties.

“This could be a new route to treating long-term inflammation and pain without the side effects of toxicity and risk of addiction observed with current treatment options,” Hsu says. “Generally, if we block inflammation, we also affect the immune response. But we’re suggesting a different approach, one where we can stop inflammation without impacting the normal immune response.”

According to Hsu, studies have demonstrated that DAGLβ inhibitors are highly effective at reducing different pain states, including neuropathic pain and chemotherapy-induced peripheral neuropathy. In the present study, the researchers uncovered a new role for DAGLβ in dendritic cells—a specialized type of innate immune cell that not only controls inflammation but also activates our body’s ability to fight infections by stimulating T cells, which produce an immune response.

“We found that by blocking DAGLβ, we can stop inflammation without affecting immunity,” Hsu says. “This supports the idea that DAGLβ 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 for fighting cancer, or, in this case, for reducing chronic inflammation and pain.