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Oxytocin: An Interplay Between Pleasure and Pain

Author: Stacy Kish

Research suggests that oxytocin neurons initially evolved as a defensive mechanism to protect against pain and injury.

Oxytocin, the ‘love’ hormone commonly associated with mother-child bonding and romance, has long been studied in association with social behaviors. But oxytocin also has a less well-understood side.

“We approached this study from the pain angle,” begins Adam Douglass, Ph.D., assistant professor in neurobiology and anatomy at University of Utah Health and senior author on the paper. “We are interested in reconciling these two functions of oxytocin [pleasure and pain] to explore if there is some overlap between these behaviors and cognitive processes.”

Previous studies have shown that oxytocin enhances fear, pain and defensive response in rodents and humans. Douglass led a team of researchers to explore this relationship in the oxytocin neural network of zebrafish. The results are available online in the July 29 issue of Nature Neuroscience.

Douglass focused on young zebrafish because the hypothalamus where this neurotransmitter triggers is buried deep on the underside of the brain, making it hard to access in most other animals.

“Larval zebrafish brains are smaller, only about 100,000 neurons,” Douglass said. “Even though the hypothalamus is in relatively the same place, there is only 1mm of tissue lying on top of it, offering a degree of access that is unavailable in other mammalian model systems.”

The team exposed the fish to a drug that acutely elicits a pain response without harming the animals, when exposed to light. Using calcium imaging, they watched in real-time as the oxytocin neurons of the fish fired. To their surprise, almost half of the neurons responded to the painful stimulus within a fraction of a second. The neurons fired before the fish responded with high-angle tail bends and thrashing behavior characteristic of a fleeing response.

Given such timing, the authors wondered if these oxytocin neurons could be driving the defensive responses. To explore this relationship further, the team engineered the oxytocin neurons of the zebrafish with a gene encoding for channelrhodopsin, a photoactive protein that artificially activates neurons in the presence of light.

This time the team only exposed those engineered oxytocin neurons to light to determine what happened when the neurons were activated directly, without the painful stimulus. The effect was the same. The fish produced behavior associated with the pain response. Thus, the oxytocin neural circuit can directly induce pain behavior in larval zebrafish. Such rapid responses to pain are likely crucial for the fish’s survival.

“Pain is a very relatable stimulus, and here we show that the brain circuits involved in controlling pain responses might be more similar between fish and mammals than previously imagined,” said Caroline Wee, Ph.D., a research fellow at the Institute of Molecular and Cell Biology, Singapore and first author on the paper. She carried out the research while at Harvard University. “Our results suggest that oxytocin should be a more prominent focus in the study of pain and pain-related diseases, and likely also in stress and anxiety disorders.”

While previous studies show that oxytocin has some analgesic properties, the results of this study show it also plays an integral role in pain response and sensitivity. According to Douglass, it is all about the timing.

“Most of what has been done in mammals is looking at much longer timescales where oxytocin levels can be chronically elevated or decreased,” he said. “Those changes are important in decreasing sensation to pain with time.”

In the future, Douglass wants to understand whether oxytocin might reduce pain on longer timescales.

“This could help us create robust therapeutics to treat pain that no one had given any thought to until very recently,” Douglass said.


Douglass and Wee are joined on this study by Maxim Nikitchenko, Erin Song, James Gagnon, Owen Randlett, Isaac Bianco, Alix Lacoste, Elena Glushenkova, Alexander Schier, Samuel Kunes and Florian Engert at Harvard University and Wei-Chun Wang, Joshua Barrios and Sasha Luks-Morgan at U of U Health. The work received funding from the Sloan Foundation, the National Institutes of Health and the Simons Foundation.