A team of researchers from Virginia Commonwealth University (VCU), the University of Texas at Austin (UT Austin), and the University of Virginia (UVA) is now on the verge of developing a promising opioid-free drug candidate for chronic pain treatment (via Medical Xpress).
This breakthrough offers hope for millions of individuals suffering from chronic pain, providing a safer alternative to highly addictive opioids.
(Photo : Scott Olson/Getty Images) CHICAGO, ILLINOIS - JULY 09: In this photo illustration, Avkare metformin ER 500 mg tablets are shown on July 09, 2020 in Chicago, Illinois.
Addressing Drug Abuse Among Chronic Pain Patients
Chronic pain affects millions globally, yet a non-addictive, reliable drug remains elusive. Opioids, though effective for severe pain, are notoriously addictive and have contributed to widespread substance abuse and overdose crises.
Alarmingly, US studies indicate that 9% to 41% of chronic pain patients abuse opioids, with 14% to 34% turning to illegal drugs.
In their recent study, published in the Proceedings of the National Academy of Sciences, the researchers found that their drug candidate, KT109, effectively reduces pain by targeting the immune system to shut off inflammatory responses.
Aron Lichtman, Ph.D., a professor at VCU's School of Medicine, explained that when the endocannabinoids in our bodies trigger inflammation, our nerves become more sensitive.
As a result, they respond more quickly with minimal stimulation, leading to situations where normally non-painful stimuli become highly painful, much like the sensation experienced during a severe sunburn.
KT109 blocks the activity of an enzyme called diacylglycerol lipase-beta (DAGLβ), which is crucial in producing endocannabinoids that regulate inflammation. The inhibitor was developed by Ken Hsu, Ph.D., an associate professor in the Department of Chemistry at UT Austin, during his postdoctoral fellowship at The Scripps Research Institute.
The researchers uncovered that disrupting DAGLβ activates liver kinase B1 (LKB1) on the cell membrane, which in turn boosts the activity of AMP-activated protein kinase (AMPK).
AMPK plays a vital role in regulating the energy state of immune cells, such as macrophages. The activation of AMPK helps control inflammation and alleviate pain.
Mice without the DAGLβ enzyme exhibited pain relief, which was reversed when AMPK was inhibited, highlighting the enzyme's role in pain management.
Lichtman explained that their process has been a bottom-up discovery, beginning with an understanding of the inhibitor at the molecular level. The new study focused on gaining a deeper insight into the inhibitor's effects on cellular and behavioral levels.
A Closer Look
Interestingly, the researchers found that KT109 controls inflammation through an additional pathway, explaining its effectiveness in treating various types of pain.
"When you inhibit DAGLβ, your immune cells are tricked into thinking they are starving," said Hsu. This change in energy metabolism turns off inflammatory signaling, similar to how the drug metformin, used for diabetes, also manages pain.
The team's inhibitor primarily targets immune cells, avoiding unnecessary reactions in other cells that might lead to side effects. Hsu emphasized, "You're going to affect these pathways where it matters, where the inflammation is happening."
While the research is currently at the preclinical stage, the goal is to develop an oral form of the drug to ensure easier administration and better patient compliance. The team aims to refine the chemistry to reduce the required dosage frequency while maintaining its pain-relieving efficacy.
