A new study provides insight into how the opioid analgesic fentanyl induces autism-like behavior
One of the most often administered analgesics in hospitals is fentanyl, a mu-opioid receptor agonist that has the potential to permanently damage rats’ behavior and sensorimotor abilities. It is unknown, however, if fentanyl usage contributes to the development of autism. Researchers from Massachusetts General Hospital (MGH), Shanghai 10th People’s Hospital, and the University of Pennsylvania have shown in an animal study that fentanyl can cause alterations in young male and female mice that are comparable to behaviors seen in autism. The results have been published in the British Journal of Anaesthesia.
Other studies have demonstrated that N-methyl-D-aspartate receptor dysfunction contributes to autism. Autism is linked to variations in the Grin2a and Grin2b genes, which encode the GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor. Autism also affects the anterior cingulate cortex of the brain.
The current study found that fentanyl causes autistic-like behaviors in young male and female mice by activating the mu-opioid receptor in the anterior cingulate brain. Furthermore, these fentanyl-induced autistic-like behaviors seem to be partially driven by the reduction of Grin2b expression in the mice’s anterior cingulate cortex induced by hypermethylation.
“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, Ph.D., the paper’s senior author and a professor of Psychiatry at Shanghai 10th 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 10th 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, Ph.D., co-first author, and an assistant professor at Shanghai 10th People’s Hospital.
Co-senior author Zhongcong Xie, MD, Ph.D., 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 10th 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 study was funded by the Ministry of Science and Technology of the People’s Republic of China, the National Natural Science Foundation of China, and Harvard Medical School.
Reference: “Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b” by Zhihao Sheng, Qidong Liu, Chun Cheng, Mengzhu Li, Jed Barash, W. Andrew Kofke, Yuan Shen and Zhongcong Xie, 11 June 2022, British Journal of Anaesthesia.
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