An international team of researchers has discovered the neural mechanisms by which sound reduces pain in mice. The findings, which could help develop safer pain relief methods, were published in Science. Researchers from the National Institute of Dental and Craniofacial Research (NIDCR), the University of Science and Technology of China, Hefei, and Anhui Medical University in Hefei, China, led the study. The National Institutes of Health includes the NIDCR.

How sound alleviates pain in mice
Neuron illustration (stock image). Credit: ktsdesign / stock.adobe.com

“We need more effective methods of managing acute and chronic pain,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D., “and that begins with gaining a better understanding of the basic neural processes that regulate pain.” “By elucidating the circuitry that mediates the pain-relieving effects of sound in mice, this study adds critical knowledge that could eventually inform new approaches to pain therapy.”

Human studies dating back to 1960 have shown that music and other types of sound can help relieve acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. However, it was unclear how the brain produces pain relief, or analgesia.

“Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia,” said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR. “We can more fully explore and manipulate the circuitry in animals to identify the neural substrates involved.”

The researchers first subjected mice with inflamed paws to three types of sounds: a pleasant piece of classical music, an unpleasant reinterpretation of the same piece, and white noise. Surprisingly, when played at a low intensity relative to background noise (about the level of a whisper), all three types of sound reduced pain sensitivity in mice. Higher intensities of the same sounds had no effect on the pain responses of the animals.

“We were really surprised that sound intensity, rather than sound category or perceived pleasantness, would matter,” Liu said.

The researchers used non-infectious viruses coupled with fluorescent proteins to trace connections between brain regions in order to investigate the brain circuitry underlying this effect. They discovered a path from the auditory cortex, which receives and processes information about sound, to the thalamus, which serves as a relay station for sensory signals from the body, including pain. Low-intensity white noise reduced the activity of neurons at the receiving end of the pathway in the thalamus in freely moving mice.

In the absence of sound, suppressing the pathway with light- and small molecule-based techniques mimicked the pain-blunting effects of low-intensity noise, whereas activating the pathway restored animals’ pain sensitivity.

It is unknown whether similar brain processes are involved in humans, or whether other aspects of sound, such as perceived harmony or pleasantness, are important for human pain relief, according to Liu.

“We don’t know if human music has any meaning to rodents, but it has a lot of emotional components,” he said.

The findings may provide scientists with a starting point for future research to determine whether the animal findings apply to humans, and may eventually inform the development of safer alternatives to opioids for treating pain.

The NIDCR Division of Intramural Research provided funding for this study. The National Key Research and Development Program of China Brain Science and Brain-Like Intelligence Technology, the National Natural Science Foundation of China, the Science Fund for Creative Research Groups of the National Natural Science Foundation of China, the CAS Project for Young Scientists in Basic Research, the Natural Science Foundation of Anhui Province, and the University of Science and Technology of China Research Funds of the Double First-Class Initiation of the University of Science and Technology of China all provided funding.

Source: Materials provided by NIH/National Institute of Dental and Craniofacial Research.

DOI: 10.1126/science.abn4663

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