Pain is an important physiological response in living organisms. While physical pain is an outcome of tissue damage, pain can manifest as diverse unpleasant sensory and emotional experiences.

Many studies report that emotional or psychological stress enhances pain responses. Furthermore, mice housed with other mice experiencing inflammatory pain exhibit a ‘bystander effect’ with heightened pain sensitivity, or “hyperalgesia.” However, the effects that underpin social pain transmission remain elusive.

Rodents emit ultrasonic vocalizations in the form of high-pitched squeaks in response to various stimuli, including pain, in both audible and ultrasound frequencies that are inaudible to humans. Recently, a team of researchers led by Assistant Professor Satoka Kasai from the Department of Pharmacy, Tokyo University of Science (TUS), Japan, conducted a series of experiments to understand how ultrasonic vocalizations emitted by mice in response to pain stimuli affect the other mice. The study, published in the journal PLOS One, was co-authored by Professor Satoru Miyazaki, Professor Akiyoshi Saitoh, (the late) Professor Satoshi Iriyama, and Professor Kazumi Yoshizawa, all from TUS.

Giving further insight into their exciting findings, Asst. Prof. Kasai explains, “In this study, we demonstrate for the first time that ultrasonic vocalizations emitted by mice in response to pain stimuli induce emotional transmission and hyperalgesia in other mice. These mice exhibit hypersensitivity that arises without injury or direct painful stimulation but is instead triggered by exposure to sound stress.”

The researchers recorded and extracted the ultrasonic range from stress calls emitted by mice experiencing pain and exposed naïve mice to the sound stress in a soundproof box in the absence of other external stressors or stimuli. Next, they evaluated the mechanical/tactile sensitivity of mice by using von Frey filaments of different stiffness to gauge the threshold that elicits the animals’ hind paw withdrawal. Notably, exposure to sound stress led to hyperalgesia, measured by a decrease in the paw withdrawal threshold.

Further, to elucidate the molecular mechanisms underlying sound stress-induced hyperalgesia, the researchers performed a microarray analysis, a technique used to assess gene expression. They found that sound stress exposure led to the upregulation of 444 genes (particularly prostaglandin-endoperoxidase synthase 2 and C-X-C motif chemokine ligand 1) and downregulation of 231 genes in the brain tissue compared to control.

Further, functional and molecular pathway analysis revealed that the differentially expressed genes were related to inflammatory and lipopolysaccharide response and the tumor necrosis factor signaling pathway, suggesting their potential role in sound stress-induced hyperalgesia.

Treatment with anti-inflammatory (pain-relieving) agents following exposure to sound stress significantly suppressed pain responses. Additionally, exposure to sound stress prolonged pain in a mouse model of inflammation. Conversely, treatment with anti-inflammatory agents attenuated pain responses exacerbated by sound stress in mice with heightened inflammation, thus corroborating the demonstrated association between sound stress, inflammation, and pain.

Overall, these findings shed light on how sound stress can induce hyperalgesia and exacerbate inflammation and pain responses. In the current study, mice were exposed solely to sound stress in the absence of other sensory stimuli such as sight, smell, or contact, suggesting that social pain transfer can occur through sound exposure alone.

These results highlight the impact of social or environmental factors on chronic pain or stress-related pain persistence. Additional studies are needed to understand how different sounds that reflect different mental or emotional states influence pain responses in different regions of the brain.

Nevertheless, these findings highlight the importance of medical environments free from stressful sounds that can induce brain inflammation and worsen pain or recovery. Additionally, the study paves the way for the exploration of ultrasound-induced neuroinflammatory mechanisms involved in pain perception and pain modulation using ultrasonic exposure.

Asst. Prof. Kasai concludes by saying, “In addition to inducing inflammation in the brain that leads to hyperalgesia, sound stress also exacerbates inflammatory pain and may interfere with pain-relieving treatments. Our research can help improve the understanding of stress-related pain and guide the development of new, scientifically based pain management treatment strategies.”

Overall, these findings provide novel insights into mental health, pain perception, and emotional empathy, explaining why some individuals feel more pain on seeing or hearing others in pain.