An international team of scientists has identified the neural mechanisms through which sound blunts pain in mice. The newly reported research, led by teams at the National Institute of Dental and Craniofacial Research (NIDCR); the University of Science and Technology of China, and Anhui Medical University, demonstrates that pain relief by sound is not purely attributable to stress reduction and distraction. The investigators suggest that their findings could inform the development of safer methods to treat pain.

Yuanyuan (Kevin) Liu, PhD, a Stadtman tenure-track investigator at NIDCR Science, and colleagues reported their results in Science, in a paper titled “Sound induces analgesia through corticothalamic circuits.” In their paper the team concluded, “This study suggests a complement for the classic pain sensation pathway that is implicated in the effect of sound on pain processing and could expedite the study of music-induced analgesia. In the future, these findings could spur the development of alternative interventions for treating pain.”

Dating back more than 60 years, studies in humans have shown that music and other kinds of sound can help alleviate acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. “As early as 1960, there were accounts from dental operations showing that music and noise can induce analgesic effects,” the authors wrote. However, how the brain produces this pain reduction, or analgesia, was less clear. “Because diverse genres of music and even nature sounds can relieve pain to an equal extent, the inherent characteristics of music or contextual factors—that is, not only to music per se—have been hypothesized to drive these analgesic effects,” the researchers noted. “However, it is still unknown how it works … The neural circuit responsible for processing sound-induced analgesia has long remained elusive.”

Functional magnetic resonance imaging (fMRI) studies have implicated changes in the activity of multiple brain areas mediating pain processing in humans exposed to music. Given the results of prior studies, the team hypothesized that the thalamus might act as a “bridge” for audio-somatosensory processing. However, they further noted, “the precise cell type–specific organization and the function(s) of the thalamic circuits mediating sound-induced analgesia remain largely unknown.”

Co-senior author Liu suggested that more in depth investigations in animals might provide new insights. “Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia, but these are only associations. In animals, we can more fully explore and manipulate the circuitry to identify the neural substrates involved.”

For their reported study the researchers first exposed mice with inflamed paws to three types of sound: a pleasant piece of classical music, an unpleasant rearrangement of the same piece, and white noise. Surprisingly, they found that all three types of sound, when played at a low signal to ambient noise ratio (SNR)—about the level of a whisper; 5-decibels—reduced pain sensitivity in the mice.

Higher intensities of the same sounds had no effect on animals’ pain responses. “In mice, we found that sound-induced analgesia depended on its low SNR rather than harmony, which is supported by a previous hypothesis that music-induced analgesia is attributable to contextual factors of the treatment, not only to the music per se,” they wrote. “We were really surprised that the intensity of sound, and not the category or perceived pleasantness of sound would matter,” Liu said.

To explore the brain circuitry underlying this effect, the researchers used non-infectious viruses coupled with fluorescent proteins to trace connections between brain regions. They found that the sound caused analgesia by inhibiting inputs from the auditory cortex auditory cortex, which receives and processes information about sound, to the thalamus, which acts as a relay station for sensory signals, including pain, from the body. In freely moving mice, low-intensity white noise reduced the activity of neurons at the receiving end of the pathway in the thalamus. “Viral tracing, microendoscopic calcium imaging, and multitetrode recordings in freely moving mice showed that low-SNR sounds inhibited glutamatergic inputs from the auditory cortex (ACxGlu) to the thalamic posterior (PO) and ventral posterior (VP) nuclei,” they explained.

Sound reduces pain in mice by lowering the activity of neurons in the brain’s auditory cortex (green and magenta) that project to the thalamus. [Wenjie Zhou]
In the absence of sound, suppressing the pathway with light- and small molecule-based techniques mimicked the pain-blunting effects of low-intensity noise, while turning on the pathway restored animals’ sensitivity to pain. “Optogenetic or chemogenetic inhibition of the ACxGlu→PO and ACxGlu→VP circuits mimicked the low-SNR sound–induced analgesia in inflamed hindpaws and forepaws, respectively. Artificial activation of these two circuits abolished the sound-induced analgesia.”

 

The authors further stated that the observed low-SNR sound–induced analgesia is “unlikely to result from some reduction in anxiety or stress, and it probably does not directly involve attention-distraction in affecting pain perception, given that the analgesic effects persisted for at least two days after sound withdrawal.”

Liu said it is unclear if similar brain processes are involved in humans, or whether other aspects of sound, such as its perceived harmony or pleasantness, are important for human pain relief. “We don’t know if human music means anything to rodents, but it has many different meanings to humans—you have a lot of emotional components,” he said.

The reported results could give scientists a starting point for studies to determine whether the animal findings apply to humans, and ultimately could inform development of safer alternatives to opioids for treating pain. “We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain,” said NIDCR Director Rena D’Souza, PhD. “By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy.”

In a perspective published in the same issue of Science, Rohini Kuner, PhD, and Thomas Kuner, PhD, at Heidelberg University, stated, “Although this experimental paradigm is not equivalent to using music and pleasant sounds to evoke analgesia in humans, the study of Zhou et al. opens up new directions for research on sound-induced analgesia by creating a model in which the mechanistic underpinnings can be investigated.”

Moreover, they noted, “The interaction between sound and pain is a double-edged sword, so caution in in­terpreting these data is warranted. Certain sounds can trigger pain, such as headaches, or intensify the pain experience, such as pho­nophobia, which is common to migraines.”