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When modified using a process known as epoxidation, two naturally occurring lipids are converted to potent agents that target multiple cannabinoid receptors in neurons, interrupting pathways which promote inflammation and pain, researchers report. These modified compounds, called epo-NA5HT and epo-NADA, have much stronger effects than the molecules from which they are derived, which also modulate inflammation and pain.
The work is part of a long-term effort to understand the potentially therapeutic byproducts of lipid metabolism, a largely neglected area of research, said University of Illinois Urbana-Champaign comparative biosciences professor Aditi Das, who led the study.
Researchers tend to think of these molecules as metabolic byproducts,”but the body is using them for signaling procedures,” Das said. “I want to learn the identity of those metabolites and figure out what they are doing.”
Our bodies use a lot of genes for lipid metabolism, and people don’t know what these lipids do. When we consume things like polyunsaturated fatty acids, within a few hours they are transformed into lipid metabolites in the body.”
Aditi Das, Affiliate, Beckman Institute for Advanced Science and Technology, Cancer Center, Illinois
When triggered, cannabinoid receptors 1 and 2 tend to reduce inflammation and pain, while a third receptor, TRPV1, promotes the sensation of pain and leads to inflammation. These receptors work together to regulate the body’s responses to disease or injury.
“Recognizing pain regulation in the body is important because we know we’ve got an opioid crisis,” Das said. “We’re searching for lipid-based options to opioids that may interact with the cannabinoid receptors and in the future be used to design therapeutics to decrease pain.”
Previous research identified two lipid molecules, known as NA5HT and NADA, that naturally suppress inflammation and pain. Das and her colleagues found that brain cells have the molecular machinery to epoxidize NA5HT and NADA, converting them to epo-NA5HT and epo-NADA. Further experiments revealed that these two epoxidated lipids are often more potent than the precursor molecules in their interactions with the cannabinoid receptors.
“For instance, we discovered that epo-NA5HT is a 30-fold stronger antagonist of TRPVI than NA5HT and shows a significantly stronger inhibition of TRPV1-mediated responses in neurons,” Das said. It inhibits pathways associated with pain and inflammation, and promotes anti-inflammatory pathways.
The team was not able to determine whether neurons naturally epoxidate NA5HT and NADA in the mind, but the findings hold promise for the future evolution of lipid compounds that can combat pain and inflammation without the harmful side effects associated with opioids, Das said.
University of Illinois at Urbana-Champaign
