LAUSR

Pain is one of the most common clinical symptoms and a leading cause of disability worldwide (GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). Furthermore, pain is closely associated with various emotional disorders, including anxiety and depression, which may, in turn, heighten pain intensity and prolong its duration (Bair et al., 2003). In previous studies, we identified the neural circuits underlying chronic pain-induced depression and anxiety as well as depression-induced allodynia (Zhou et al., 2019; Zhu et al., 2021). However, due to the complexity of its pathogenesis, therapeutic development remains unsatisfactory, and the discovery of appropriate treatments for pain represents a major and ongoing clinical challenge (Hill et al., 2011). Music therapy, as a non-pharmacological intervention for pain management, has attracted considerable attention due to its striking analgesic effects, as well as its safety, ease of use, and applicability to many individuals (Lunde et al., 2019). Sound-induced analgesia was reported in dental operations as early as the 1960s (Gardner et al., 1960). Studies have since shown that diverse genres of music, and even sounds from nature, can relieve pain to an equal extent. Thus, the inherent characteristics of music or sound-related environmental factors, that is, not exclusively vocal or instrumental music per se, have been hypothesized to drive these analgesic effects. Functional magnetic resonance imaging (fMRI) in humans exposed to music has revealed changes in the activity of multiple brain areas known to mediate pain processing. However, the neural substrates underpinning the cross-modal audio-somatosensory interactions that may be responsible for sound-induced analgesia remain unclear. In a recent paper published in Science (Zhou et al., 2022), we identified neural circuits that mediate sound-induced analgesia in the brains of mice. To determine whether sound could induce analgesia in mice, we initially delivered consonant sound (e.g., pleasant music for humans) to mice subjected to pain induced by administration of complete Freund’s adjuvant (CFA) at sound pressure levels (SPL) of 50 and 60 dB (ambient noise at 45 dB SPL). Surprisingly, only 50 dB sound exposure, but not 60 dB sound exposure, induced analgesia. Next, to determine whether consonant sound harmony was required to induce analgesia in mice, we replaced the consonant sound with dissonant sound (unpleasant music for humans created by electronically modifying consonant excerpts) or white noise, with comparable results obtained for all three sounds. As musicinduced analgesia in humans may be attributed to the treatment environment, we conducted pain measurements in the context of different ambient noises and found that the decisive factor in eliciting pain relief was a 5-dB increase in sound intensity relative to ambient noise levels (sound-tonoise ratio, SNR). We next investigated the neural circuitry through which sound exerts its analgesic effects. Sound signals are collected by the cochlea and then transmitted to the cochlear nucleus, superior olivary, medial geniculate body, and finally to the auditory cortex (ACx). The ACx analyzes perceived signals and subsequently projects to other nuclei to mediate learning, escape behavior, frequency discrimination, and musical pleasure, among others (Schreiner & Winer, 2007). Therefore, we examined the potential role of the ACx in sound-induced analgesia. In vivo multi-tetrode recordings showed that 5 dB SNR sound inhibited neuronal activity in the ACx. Chemogenetic inhibition of glutamatergic neurons in the ACx (ACxGlu) significantly increased the nociceptive threshold in inflammatory pain model mice. Furthermore, viral tracing revealed that ACxGlu neurons projected to the posterior (PO) and ventral posterior (VP) nuclei of the somatosensory thalamus, both of which relay nociceptive information. We then investigated whether these two circuits also participated in 5 dB SNR sound-induced analgesia. Based on