Synthetic opioids can treat inflammatory bowel disease by targeting immune system head-on

TOKYO, Japan — Although synthetic opioids come with a serious risk of causing addiction or overdose, a recent study finds the painkillers may provide a new treatment option for people with inflammatory bowel disease. Researchers in Japan suggest that the medication KNT-127 may be an effective therapy for IBD due to its ability to operate directly on immune cells and lessen the intensity of inflammation.

This is also a significant step forward in our knowledge of the “brain-gut axis” — the link between the central nervous system (CNS) and gut function.

Opioids operate by binding to proteins called opioid receptors on nerve cells in the brain, spinal cord, stomach, and other regions of the body. As a result, opioids impede the transmission of pain signals from the spinal cord to the brain. Drug manufacturers derive some of the most well-known opioids from plants, like morphine. However, companies also produce other opioid compounds, such as endorphins, using synthetic chemicals in labs.

KNT-127 improves bowel function in mice

In the study, researchers tested the impact of KNT-127, an artificially produced opioid, on immunological activity in live animals and cultured cells. This drug reduced the intensity of the inflammatory disease known as colitis. Mice with IBD displayed decreased weight loss and colon regression while on the drug. Additionally, they showed a reduction in the progression of the disease and an increased function of the bowels.

According to Prof. Chiharu Nishiyama, lead researcher from the Tokyo University of Science, one of the major goals of the experiment was making sure KNT-127 alone was responsible for these results.

“Before proceeding with additional experiments, we had to rule out the role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,” Nishiyama says in a university release.

To do so, they used YNT-2715, which is a peripheral KNT-127 that can’t penetrate the blood-brain barrier. This compound produced identical results as KNT-127, demonstrating that the anti-inflammatory properties of KNT-127 were not a result of the CNS, rather the drug itself.

New drug rebalances the immune system

Additionally, KNT-127 lowered levels of IL-6, a pro-inflammatory cytokine, and the number of macrophages in mesenteric lymph nodes (MLNs). After therapy, the team also noticed an abundance of regulatory T cells (Tregs) in the MLNs.

“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,” says Prof. Hiroshi Nagase from the University of Tsukuba and the chief drug developer behind the synthetic opioid. “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.”

The team feels optimistic about the future as a result of reaching this important achievement.

“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,” Prof. Nishiyama adds.

The study is published in the journal Frontiers in Immunology.

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