Acoustic motor cortex stimulation enhances the descending analgesic pathway to alleviate chronic pain in mice

Chronic pain poses considerable health risks, necessitating the development of effective treatments. Physical modulation of the motor cortex has demonstrated promise for pain relief; however, existing methods require invasive electrode implantation or have limited spatial resolution. Therefore, we developed a non-invasive, high-precision acoustic motor cortex stimulation (aMCS) system to alleviate chronic pain and explore its mechanisms. We developed a wearable aMCS system and employed the spared nerve injury (SNI) method to establish a mouse model of chronic pain. The model mice underwent aMCS with different acoustic parameters, and their pain behaviors were systematically evaluated. Subsequently, we established a long-term spinal cord two-photon system to monitor the effects of aMCS on spinal cord dorsal horn (SCDH) neuronal activity. Next, TRAP2-tdTomato mice were used to examine the effects of aMCS on the motor cortex and other regions of the descending analgesic pathway. Finally, we conducted magnetic resonance imaging, histology, and temperature monitoring to evaluate the safety of aMCS. aMCS with specific parameters significantly ameliorated pain behaviors in a mouse model of chronic pain. Two-photon calcium imaging indicated that aMCS reduced the intensity of neuronal activity in SCDH. Activity mapping in TRAP2-tdTomato mice revealed that aMCS enhanced neuronal activity in the primary motor cortex and zona incerta while diminishing it in the lateral periaqueductal gray and SCDH. Safety assessments confirmed the absence of deleterious effects on the stimulated region. aMCS provides a novel, non-invasive and effective approach to alleviating chronic pain by potentially enhancing the descending analgesic pathway.