Study may lead to alternative treatment for potentially addictive opioid pain killers

When two naturally occurring lipids are altered using a process called epoxidation, they are transformed into powerful agents that target numerous cannabinoid receptors in neurons, disrupting pathways that promote inflammation and pain.

Comparative biosciences professor Aditi Das led a study of modified lipids that target the body's endocannabinoid system, which is involved in regulating pain and inflammation. Image Credit: L. Brian Stauffer.

Called epo-NADA and epo-NA5HT, these modified compounds, have relatively more potent effects than the molecules from which they are obtained, which also control inflammation and pain.

The study, published in the Nature Communications journal, creates new research opportunities in the effort to identify novel alternatives to opioid pain killers that are potentially addictive.

The study is part of a long-term effort to interpret the possibly therapeutic byproducts of lipid metabolism, a predominantly neglected field of research, stated Aditi Das, comparative biosciences professor from the University of Illinois Urbana-Champaign and who also headed the research work.

Although many individuals value the role of dietary lipids, like omega-3 and omega-6 fatty acids in supporting health, the human body changes these fat-based nutrients into other forms, and a few of these also play a key role in the healthy functions of tissues, cells, and organ systems.

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, Study Lead and Comparative Biosciences Professor, University of Illinois Urbana-Champaign

Professor Das is also an affiliate of the Beckman Institute for Advanced Science and Technology and of the Cancer Center at Illinois.

Investigators tend to think of these molecules as metabolic byproducts,

Professor Das continued, “But the body is using them for signaling processes, I want to know the identity of those metabolites and figure out what they are doing.”

Along with her collaborators, she targeted the endocannabinoid system, since cannabinoid receptors on cells across the body play a key role in controlling pain. When cannabinoid receptors 1 and 2 are stimulated, they tend to decrease inflammation and pain, while a third receptor, called TRPV1, supports the sensation of pain and plays a key role in inflammation; and these receptors work together to regulate the body’s responses to disease or injury.

Understanding pain regulation in the body is important because we know we have an opioid crisis. We’re looking for lipid-based alternatives to opioids that can interact with the cannabinoid receptors and in the future be used to design therapeutics to reduce pain.”

Aditi Das, Study Lead and Comparative Biosciences Professor, University of Illinois Urbana-Champaign

Two lipid molecules, called NADA and NA5HT, were identified in a previous study and these molecules naturally inhabit inflammation and pain. Das and her collaborators found that cells in the brain have the molecular machinery needed to epoxidize NADA and NA5HT, changing them to epo-NADA and epo-NA5HT, respectively.

Additional experiments showed that both these epoxidated lipids are several times more powerful than the precursor molecules in their interactions with the cannabinoid receptors.

For example, we found that epo-NA5HT is a 30-fold stronger antagonist of TRPVI than NA5HT and displays a significantly stronger inhibition of TRPV1-mediated responses in neurons.”

Aditi Das, Study Lead and Comparative Biosciences Professor, University of Illinois Urbana-Champaign

The epo-NA5HT compound blocks pathways linked to pain and inflammation, and supports anti-inflammatory pathways.

The researchers were unable to find out whether neurons naturally epoxidate the NADA and NA5HT lipid molecules in the brain; yet, the findings show promise for the upcoming development of lipid compounds that can fight inflammation and pain without the adverse side effects linked to opioids, Das concluded.