Intriguing new preclinical research from a team of Japanese scientists has found targeting opioid receptors in the gut could be a new treatment for inflammatory bowel disease. The research builds on early evidence showing a relationship between opioids and immune cell function.

For several years scientists have noticed links between opioid use and immune suppression. Observational studies have noted some hospital patients treated with opioids were more vulnerable to viral infections, while in vitro research has demonstrated opioids can influence immune cell function. But exactly what is going has been unclear.

There has long been a noted connection between opioids and the gut, but only relatively recently have researchers discovered opioid receptors are not isolated to the brain. This new research set out to better understand how opioids interact with the immune system by focusing on a mouse model of inflammatory bowel disease.

The researchers focused on a previously developed drug called KNT-127, which is designed to selectively stimulate delta opioid receptors only. Drugs specifically targeting delta opioid receptors have recently been receiving plenty of research attention in the hope they work effectively as pain relievers without negative side effects such as respiratory depression or dependency often seen with currently available opioid drugs.

The new study, published in the journal Frontiers in Immunology, first revealed KNT-127 effectively reduced the severity of colon inflammation in several mouse models. A number of different experiments showed the experimental opioid directly suppressing immune cell activity.

Nagata et al (2021), Frontiers in Immunology

But a key question remained – was the drug exerting its anti-inflammatory effects by directly activating delta opioid receptors in the gut, or were receptors in the brain playing a role?

To answer this question the researchers looked to a different version of KNT-127 designed to be unable to cross the blood-brain barrier. Similar results were seen in the mouse models, affirming the anti-inflammatory activity of the drug was independent of any central nervous system (CNS) actions.

“Several people around the world suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking,” says Hiroshi Nagase, an author on the new study. “Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for such diseases.”

Nagase does stress there is plenty more work needed before these findings can be translated into a clinical treatment for human patients. However, the study offers some of the first clear evidence of opioid receptors in the gut being involved directly in inflammatory responses.

Chiharu Nishiyama, from the Tokyo University of Science and lead researcher on the new study, says these findings offer compelling insights into gut-brain connections.

“Today, we know that poor mental health has physical manifestations,” explains Nishiyama. “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.”

The new study was published in the journal Frontiers in Immunology.

Source: Tokyo University of Science