Researchers led by a team at the University of Illinois Urbana-Champaign have found that two naturally occurring lipids can be converted, via a cellular process known as epoxidation, into potent agents that target multiple cannabinoid receptors in neurons, to interrupt pathways that promote pain and inflammation. The modified compounds, called epo-NA5HT and epo-NADA, have much more powerful effects than the molecules from which they are derived—N-arachidonoyl-dopamine (NADA) and N-arachidonoyl-serotonin (NA5HT)—which can also act to regulate pain and inflammation.

Reported in Nature Communications, the team’s study opens a new avenue of research in the effort to find alternatives to addictive opioid pain killers. “Understanding pain regulation in the body is important because we know we have an opioid crisis,” said study lead Adita Das, PhD, a University of Illinois Urbana-Champaign comparative biosciences professor. “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.”

Das and colleagues reported on their findings in a paper titled, “Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel,” in which they concluded, “The epoxide metabolites are bioactive lipids that are potent, multi-faceted molecules, capable of influencing the activity of CB1, CB2, and TRPV1 receptors … These molecules are potential candidates for the development of pain therapeutics.”

Opioids are highly addictive pain medications that are susceptible to abuse, the authors wrote. They cite CDC figures indicating that just five years ago the age-adjusted death rate by opioid overdose was nearly 20 per 100,000. “Hence, there is a need for therapeutic alternatives to opioids that combat inflammation and the associated pain.”

The newly reported work is part of a long-term effort to understand the potential therapeutic byproducts of lipid metabolism, a largely neglected area of research, said Das. While many people appreciate the role of dietary lipids such as omega-3 and omega-6 fatty acids in promoting health, the body converts these fat-based nutrients into other forms, some of which also play a role in the healthy function of cells, tissues, and organ systems.

“Our bodies use a lot of genes for lipid metabolism, and people don’t know what these lipids do,” explained Das, who is also an affiliate of the Beckman Institute for Advanced Science and Technology and of the Cancer Center at Illinois. “When we consume things like polyunsaturated fatty acids, within a few hours they are transformed into lipid metabolites in the body.”

And while scientists may think of these molecules as metabolic byproducts, in fact “… the body is using them for signaling processes,” Das said. “I want to know the identity of those metabolites and figure out what they are doing.”

Das and her colleagues focused on the endocannabinoid system, as cannabinoid receptors on cells throughout the body play a role in regulating pain. When activated, cannabinoid receptors 1 and 2 tend to reduce pain and inflammation, while a third receptor, TRPV1, promotes the sensation of pain and contributes to inflammation. These receptors work together to modulate the body’s responses to injury or disease.

“Pain is regulated primarily by sensory afferent neurons and immune cells,” the authors continued. “Both of these cell types are rich sources of lipid mediators. Lipid mediators are generated via the enzymatic oxidation of dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs).” And pro-inflammatory lipid mediators contribute to pain sensitivity by activating GPCRs in sensory neurons, which increases pain response. In contrast, anti-inflammatory and pro-resolving lipid mediators act to suppress and resolve the inflammatory process, and thus dampen inflammatory pain. “Hence, lipid mediators can fine-tune the pain response and have been at the center for the development of alternative non-opioid pain therapeutics,” the researchers stated.

Previous research identified two lipid molecules, NA5HT and NADA, which naturally suppress pain and inflammation. “These dopamine and serotonin derivatives were identified in vivo in brain and intestinal tissues,” the investigators explained. “NADA is an agonist of both CB1 and TRPV1 … NA5HT is an antagonist of TRPV1.”

Through their newly reported studies, Das and her colleagues have now shown that certain brain cells possess the molecular machinery to epoxidize NA5HT and NADA, converting them to epo-NA5HT and epo-NADA. The Das research group collaborated with Hongzhen Hu, PhD, a pain and itch researcher and professor of anesthesiology at Washington University in St. Louis, and with Univerity of Illinois biochemistry professor Emad Tajkhorshid, PhD, who helped simulate how the lipids are metabolized by enzymes known as cytochrome P450s.

Further experiments revealed that these two epoxidated lipids are many times more potent than the precursor molecules in their interactions with the cannabinoid receptors. “Altogether, we show that epoNADA and epoNA5HT act as dual CB1/2 and TRPV1 ligands and exhibit anti-inflammatory activity.”

“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,” Das said. It inhibits pathways associated with pain and inflammation, and promotes anti-inflammatory pathways.

The team could not determine whether neurons naturally epoxidate NA5HT and NADA in the brain, but the findings hold promise for the future development of lipid compounds that can combat pain and inflammation without the dangerous side effects associated with opioids, Das said. As the scientists concluded in their report, “The discovery of these molecules will serve as templates for new multi-target therapeutic drugs that will prove useful for the treatment of inflammatory pain, as well as of other conditions in which these receptors are targeted in other clinical studies.”



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