New findings suggest that opioids have the ability to control gut immune responses and thus reduce colonic inflammation, indicating that they could be used to treat immune diseases.
Opioids are a class of substances that control sensations such as pain and emotions in animals. While plant-derived Opioids are a class of drugs that help animals control sensations like pain and emotion. While the most well-known opioid narcotics are those derived from plants, such as morphine, other opioid molecules, such as endorphins, can also be synthesized by the body or developed artificially in laboratories.
Opioids work by binding to opioid receptors that are found on the surface of cells. While opioid receptors were previously thought to be restricted to the central nervous system (CNS), their recent discovery in other parts of the body has raised concerns about their effects on other organs, including the immune system.
Prof. Chiharu Nishiyama, Kazuki Nagata, and Ayumi Okuzumi of Tokyo University of Science, as well as Prof. Hiroshi Nagase of the University of Tsukuba, attempted to understand the effects of opioids on the immune system in a recent study published in Frontiers in Immunology. In live animal and cell culture experiments, they investigated the effects of KNT-127, an artificially synthesized opioid that activates delta opioid receptors.
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When mice with inflammatory bowel disease (IBD) were given KNT-127, the severity of colitis, a type of colon inflammation, was reduced, as evidenced by less weight loss and colon atrophy, as well as improved disease activity scores. In a recovery model, similar results were obtained, confirming the beneficial effects of KNT-127 against colonic inflammation.
Although these findings were promising, an important caveat still loomed.
“Before proceeding with additional experiments, we had to rule out the role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,” says Prof. Nishiyama, the lead researcher on the study.
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To test this hypothesis, the researchers used YNT-2715, a peripheral KNT-127 that cannot cross from the bloodstream to the brain. The findings were similar to those obtained with KNT-127, indicating that its anti-inflammatory properties were not dependent on the CNS.
This gave the researchers hope, so they looked into other immune-related effects of KNT-127 treatment in the colitis model. They discovered that the opioid reduced serum levels of IL-6, a pro-inflammatory factor, as well as the number of macrophages in the mesenteric lymph nodes, as the disease progressed (MLNs).
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They also noticed an increase in the number of regulatory T cells (Tregs) in MLNs, which was surprising. Their findings showed that KNT-127 suppresses macrophage-induced inflammation during disease progression and enhances Treg-mediated anti-inflammatory responses during recovery.
Finally, the researchers conducted in vitro experiments in which they treated macrophages derived from bone marrow or T cells from the spleen with KNT-127 to better understand the drug’s direct effects on immune cells. Increased secretion of pro-inflammatory signals, as well as enhanced Treg development, were found in response to KNT-127 treatment, which was consistent with findings from animal experiments.
Overall, the findings showed that KNT-127 can directly act on immune cells and reduce inflammation severity, making it a promising candidate for IBD treatment.
“Several people around the world suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking. Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for such diseases,” comments Prof. Nagase, the chief drug developer behind the synthetic opioid, while also cautioning of the road ahead.
“Of course, before these drugs are used clinically, additional experiments will be required to elucidate how they exert their immunomodulatory functions and what their effects on other immune diseases are,” he adds.
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Nonetheless, Prof. Nishiyama and her colleagues believe that their research is a significant step forward, not only in terms of IBD treatment, but also in terms of our understanding of the “brain-gut axis,” or the interrelationship between brain and gut function, which has gotten a lot of attention in recent years.
“Today, we know that poor mental health has physical manifestations. For example, stress worsens inflammation in the gut, which in turn affects the health of the brain. Our results on the immune-related effects of opioids, which commonly act on the brain, is a step toward unraveling the biological mechanisms that govern the reciprocative relationship of gut health and the immune system with the CNS,” mentions Prof. Nishiyama, excited about what the future holds.
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