Summary: Pain is not only a physical sensation but can also be transmitted socially and emotionally. New research from Tokyo University of Science shows that ultrasonic vocalizations produced by mice in pain can cause increased pain sensitivity, or hyperalgesia, in nearby mice even when those mice have no injury. This “sound stress” triggers brain inflammation, changes in gene activity, and heightened pain responses that can prolong existing pain and reduce the effectiveness of pain treatments.
The study highlights how environmental and emotional cues—specifically stressful sounds—can influence pain perception and recovery, underscoring the need to consider auditory environments in clinical settings where patients are vulnerable to prolonged or worsened pain.
Key Facts:
- Sound-induced hyperalgesia: Mice exposed to ultrasonic distress calls showed increased sensitivity to touch without receiving any direct injury.
- Inflammatory pathway activation: Exposure to those ultrasonic sounds changed gene expression patterns in the brain, with increases in inflammation-related genes.
- Clinical implications: Stressful sounds may worsen pain perception, extend recovery times, and interfere with the effectiveness of anti-inflammatory pain treatments.
Source: Tokyo University of Science
Background
Pain is a complex biological and emotional response. Beyond tissue damage, pain includes unpleasant sensory and affective experiences shaped by psychological and social factors. Previous research has shown that animals housed near peers in pain can develop heightened sensitivity—a bystander effect—but how pain signals transfer socially has not been fully understood.
Study design and methods
Assistant Professor Satoka Kasai and colleagues at the Tokyo University of Science recorded ultrasonic vocalizations emitted by mice during painful stimulation. These high-frequency calls are inaudible to humans but serve as social signals among rodents. The team isolated the ultrasonic component of these distress calls and exposed otherwise naive mice to that sound in a soundproof environment, eliminating visual, olfactory, and tactile cues.
To measure tactile sensitivity they used von Frey filaments of increasing stiffness to determine the paw withdrawal threshold. Mice exposed to the ultrasonic distress sounds showed a significant reduction in withdrawal threshold, indicating hyperalgesia. This heightened sensitivity persisted for days after exposure.
Mechanisms revealed by gene analysis
The researchers conducted DNA microarray analysis on brain tissue and found substantial changes in gene expression after sound stress exposure. A total of 444 genes were upregulated and 231 genes were downregulated compared with controls. Notably increased were inflammation-related genes such as prostaglandin-endoperoxide synthase 2 (COX-2) and C-X-C motif chemokine ligand 1 (CXCL1).
Pathway analysis linked the differentially expressed genes to inflammatory responses, lipopolysaccharide signaling, and tumor necrosis factor pathways, suggesting that the ultrasonic distress calls activated neuroinflammatory cascades associated with pain sensitization.
Pharmacological validation and effects on inflammatory pain
The study tested whether anti-inflammatory treatments could reverse sound-induced hyperalgesia. Administration of anti-inflammatory agents reduced the pain responses triggered by ultrasonic exposure. In a separate experiment using a mouse model of inflammatory pain, exposure to sound stress prolonged pain recovery and diminished the analgesic effects of an anti-inflammatory drug, supporting a causal link between sound stress, neuroinflammation, and worsened pain outcomes.
Implications
These results demonstrate that auditory social cues alone—without direct physical contact—can transfer pain-related information and induce measurable changes in the brain that increase pain sensitivity. The findings emphasize the role of environmental and emotional factors in chronic pain and suggest that minimizing stressful auditory stimuli in clinical and caregiving settings could help prevent prolonged or intensified pain.
Future research should examine how different types of sounds associated with varied emotional states influence pain processing across brain regions, and whether similar mechanisms operate in humans. Understanding ultrasound-triggered neuroinflammatory pathways may also open new directions for treating stress-exacerbated pain.
Research team
The study was led by Assistant Professor Satoka Kasai at the Department of Pharmacy, Tokyo University of Science, with co-authors Professor Satoru Miyazaki, Professor Akiyoshi Saitoh, the late Professor Satoshi Iriyama, and Professor Kazumi Yoshizawa.
Funding
The authors received research support from FUJIMIC Inc. (Tokyo, Japan) and a grant from AMED-CREST (Grant Number JP23gm1510008s0102). The sponsors did not influence the study design, analysis, or manuscript submission.
About this pain and auditory neuroscience research news
Author: Yoshimasa Iwasaki
Source: Tokyo University of Science
Contact: Yoshimasa Iwasaki – Tokyo University of Science
Image: The image is credited to Neuroscience News
Original Research: Open access. “Pain-stimulated ultrasound vocalizations and their impact on pain response in mice” by Satoka Kasai et al., PLOS One. DOI: 10.1371/journal.pone.0324730
Abstract
Pain-stimulated ultrasound vocalizations and their impact on pain response in mice
Pain combines physiological and emotional components. Emotional transmission can cause pain even without direct injury, but the mechanisms remain unclear. This study used ultrasonic recordings captured during pain stimulation in mice as a sound stressor to test effects on tactile thresholds and on an inflammatory pain model.
Tactile thresholds decreased one and three days after exposure to the ultrasonic sound stress. Microarray analysis of the thalamus revealed increased expression of inflammation-related genes, including prostaglandin-endoperoxide synthase 2 and C-X-C motif chemokine ligand 1. Inhibitors targeting these pathways, loxoprofen and SB225002 respectively, significantly reduced sound stress–induced hyperalgesia.
When sound stress was applied to mice recovering from inflammatory pain induced by complete Freund’s adjuvant, pain was prolonged and the analgesic effect of loxoprofen was attenuated. These findings indicate that ultrasonic sound stress can induce brain inflammation that causes hyperalgesia and can exacerbate inflammatory pain, complicating treatment.