A recent UNMC study finds Oxycodone use during or after pregnancy in mammals leads to compulsive behavior at least two generations down the line.
Katherine E. Odegaard led the joint study on rats between the labs of Dr. Sowmya V. Yelamanchili and Dr. Gurudutt Pendyala in UNMC’s Department of Anesthesiology. Their research brings scientists one step closer to understanding the mechanisms of opioid addiction and finding a treatment for it.
The study, published in Translational Psychiatry, is the first to show neural orexin pathway dis-regulation across multiple generations of mammals. Orexin helps regulate arousal, wakefulness and appetite. This neural dis-regulation happens when future generations are exposed to prescription opioids either in-utero or postnatally.
Some observed effects can even skip generations, only becoming apparent in the grandchildren. These effects included altered genetics, social abnormalities, anxiety, compulsive behavior and body weight modulation. The child generation tended to be underweight, while the grandchild generation were obese (measured using both BMI and Lee’s Obesity Index).
In an interview, Odegaard said experiments were performed on three generations: F0 – the parent generations that were given Oxycodone (during or after pregnancy) or a saline control, F1 – their children that weren’t treated, and F2 – the children’s children. Her team found oxycodone (OxyContin’s main ingredient) directly affected the in-utero group’s F2 generation before F1 was born.
“As the F1 generation is forming and growing inside, their gametes and reproductive organs are also developing,” she said. “So the gametes that will go on to create the F2 generation will also be directly exposed to Oxy.”
As for the F1 rats that only received Oxy after giving birth, they also passed down the effects. The children and grandchildren of these rats were exposed through breast milk instead of the placenta like the in-utero exposed rats.
In one social-preference experiment that measures social deficits in exposed rats, a test subject is placed into a three-chambered apparatus. This apparatus is composed of a central entrance, and mini-chambers on either side containing either a toy or a naïve rat — a stranger the subject hasn’t met before. After five minutes of acclimation, the doors to the mini-chambers open and the subject is allowed to freely explore for 15 minutes, Odegaard said. She said test subjects are expected to spend more time with the naïve rat and less time with their toys.
“In our F2 [generation], the IOU [in-utero] animals spent less time with the naïve animal and they had more contacts with the toy,” Odegaard said. “So they seemed to be more interested in being with the toy and by themselves than interacting with the new animal.”
Adapted from “Fig. 4: Behavior tests”, courtesy UNMC – Odegaard, et all.
Inside the brain, orexins bind to the system that regulates various behaviors – such as feeding and sleeping – and the reward system. These neural pathways and the systems they influence aren’t unique to rats; humans have them as well, Yelamanchili said.
The group measured genetic material using high-throughput RNA sequencing, according to Dr. Gurudutt Pendyala. He said that type of gene sequencing is their forte, with the help of the University’s state-of-the-art facility on campus.
They found generations F1 and F2 had altered genetics for both in-utero and postnatal groups when compared to the control. Based on the findings, the team is looking for drugs that quell the orexin pathway and treat the harmful side-effects of prescription opioids, Pendyala said.
The lab has yet to show if these addictive behaviors pass through generations F3 and onwards, and hope to find the answer in upcoming self-administration experiments,Yelamanchili said.
Alongside Odegaard, Yelamanchili and Pendyala, the research team also featured:
- Victoria L. Schaal – Co-author and technician in Pendyala’s lab, helped breed and gather measurements of F1 generation pups
- Alexander R. Clark – Technician in Yelamanchili’s lab, helped with animal behavior work and measurements
- Sneh Koul – Technician in Pendyala’s lab, helped score behavior videos
- Austin Gowen – Student in Yelamanchili’s lab, helped in post-validation of gene expressions, identifying orexin system
- Dr. Jagadesan Sankarasubramanian, Dr. Peng Xiao and Dr. Chittibabu Guda – Helped with in bioinformatic analysis
- Dr. Steven J. Lisco – Department of Anesthesiology Chair, came up with idea and contributed more ideas
- An earlier version of this story portrayed the study as being run out of just Dr. Yelamanchili’s lab. It was actually a joint study between the labs of Dr. Yelamanchili and Dr. Pendyala, and the article has been updated to reflect this.
- An earlier version of this story reported RNA sequencing for future experiments would happen on-campus. The on-campus sequencing has already occurred, so the corresponding line was deleted.