Opioid receptors play unexpected role in gut nervous system development

Researchers at Rice University have revealed a previously unknown function of opioid receptors in the development of the enteric nervous system (ENS), often referred to as the "brain in the gut." This discovery challenges conventional understanding of opioid receptors, shedding new light on their significance beyond pain management and addiction.

Led by Rosa Uribe, an assistant professor of biosciences at Rice and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar, the research team identified the genes critical for ENS development by conducting a series of experiments using zebrafish embryos, which share many genetic similarities with humans. The ENS is a network of neurons in the gastrointestinal tract that plays a vital role in regulating digestive processes.

The team's research was published in the PLOS ONE journal on May 29.

We found that the opioid signaling pathway is required for the developmental formation of nerves in the gut, an understudied part of the body called the enteric nervous system."

Rosa Uribe, assistant professor of biosciences, Rice University

Using gene-editing techniques, the researchers selectively removed, or knocked out, a single gene from an entire population of zebrafish embryos to observe how these genetic alterations affected the formation of gut nerves. This process revealed novel genes, including those encoding opioid receptors, implicated in ENS development.

Contrary to previous assumptions, the researchers found that opioid receptors are not solely involved in pain perception and addiction but are also integral to the developmental formation of gut nerves.

"When these receptors were deactivated, the migration and maturation of enteric neurons along the gut were disrupted," Uribe said. That disruption indicates the crucial role of opioid signaling pathways in ENS development.

The team's findings open up new avenues for understanding digestive health and disease. Many infants born with missing gut nerves experience difficulties in passing stool, highlighting the potential impact of this research on pediatric medicine. Understanding the role of opioids in gut development may pave the way for innovative treatments for congenital digestive disorders.

"Our research unveils a new aspect of opioid receptor function and highlights their unexpected role in gut development," Uribe said. "This could have profound implications for understanding digestive disorders and potentially lead to new therapeutic approaches."

Moreover, the study identified other genes, such as VGF, with implications for gastrointestinal health. Further research in this area could uncover more insights into the complex interplay between genes, the nervous system and digestive function, said lead researcher and postdoctoral fellow Rodrigo Moreno Campos.

"Our finding is incredible and opens up a whole new avenue of enteric neurodevelopmental biology research in the field," Moreno Campos said. "The implications for congenital, neurological and metabolic disease are great."

Uribe joined Rice in 2017 as a CPRIT Scholar. She earned a bachelor's degree in cell and molecular biology from San Francisco State University in 2006 and a doctorate in molecular cell and developmental biology from the University of Texas at Austin in 2012. In 2020, she won an NSF CAREER Award.

This study was supported by the National Institutes of Health grant R01DK124804 awarded to R.A.U., and by National Science Foundation grant 1942019 awarded to R.A.U. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.