Opioid analgesic fentanyl may cause autism-like behavior in young mice

BOSTON – Fentanyl, a mu-opioid receptor agonist, is one of the most commonly used analgesics in the hospital and may induce long-lasting behavioral and somatosensory impairment in rodents. However, whether the use of fentanyl is associated with the development of autism is not known. An animal study led by investigators at Massachusetts General Hospital (MGH), Shanghai 10^th People’s Hospital, and the University of Pennsylvania has shown that fentanyl can induce changes similar to autism-like behaviors in young male and female mice. The findings are published in the British Journal of Anaesthesia.

Research by other groups has shown that N-methyl-D-aspartate receptor dysfunction contributes to autism. Variations in Grin2a and Grin2b, the genes encoding GluN2A and GluN2B subunits of N-methyl-D-aspartate receptor, are associated with autism. In addition, the anterior cingulate cortex of the brain is affected in autism.

In this current study, the research team reported that fentanyl induces autism-like behaviors in young male and female mice via activating the mu-opioid receptor in the anterior cingulate cortex. Further, these fentanyl-induced autism-like behaviors appear partially due to the hypermethylation-mediated reduction of Grin2b expression in the anterior cingulate cortex of mice.

“Because the anterior cingulate cortex is a hub for mediating social information, we focused on the expression of Grin2b in that area,” says Yuan Shen, MD, PhD, the paper’s senior author and a professor of Psychiatry at Shanghai 10^th People’s Hospital. “We found fentanyl decreased expression of Grin2b in the anterior cingulate cortex. The overexpression of Grin2b prevents fentanyl-induced autism-like behavior in the mice. These findings suggest a potential mechanism to prevent or treat the autism-like behavior,” says Shen.

The group conducted experiments using an open field test (in which a mouse can walk inside a box) and an elevated plus-maze (in which a mouse can walk on an elevated platform) to detect the anxiety and stereotyped behaviors of mice. Using a three-chamber social preference test (in which a mouse can interact with another mouse), they also assessed potential social deficits. “We used these tests because impaired social interaction, stereotyped behaviors, and anxiety are the key feature of autism-like behaviors in mice,” says Zhihao Sheng, co-first author of the paper. Sheng is a graduate student at Shanghai 10^th People’s Hospital.

“However, the changes of mice in these behavioral tests do not equal autism in humans. These behavioral tests are only used to study the autism-like behaviors in mice because they can demonstrate certain features of behavior changes similar to the manifestation of autism,” says Qidong Liu, PhD, co-first author and an assistant professor at Shanghai 10^th People’s Hospital.

Co-senior author Zhongcong Xie, MD, PhD, adds: “There is no current evidence that fentanyl is associated with a similar effect in humans and the outcome of the animal study is not an indication to avoid fentanyl in clinical anesthesia. However, the outcome will promote further research, including clinical investigations, to determine the potential neurobehavioral influence of opioids on brain development.” Xie is director of Basic Science Research in the MGH Department of Anesthesia, Critical Care and Pain Medicine and Henry K. Beecher Professor of Anaesthesia at Harvard Medical School.

Other authors include Chun Cheng and Mengzhu Li from Shanghai 10^th People’s Hospital and Shanghai First Maternity and Infant Hospital, W. Andrew Kofke from the University of Pennsylvania, and Jed Barash, a Massachusetts neurologist.

This research was supported by the Ministry of Science and Technology of China and the National Natural Science Foundation of China.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #4 in the US News & World Report list of “America’s Best Hospitals.” MGH is a founding member of the Mass General Brigham health care system.