Auricular vagus nerve stimulation drives analgesia via an auricle–brain axis in a mouse model of neuropathic pain

Despite its long-recognized effects in relieving pain, the neural substrates of auricular stimulation remain elusive. Here, we show that trans-auricular vagus nerve stimulation (taVNS), i.e., electrical stimulation of the auricular concha, effectively induces analgesia in a mouse model of neuropathic pain. Viral tracing, microendoscopic calcium imaging, and multi-electrode recordings reveal that auricular vagal signals travel to the jugular-nodose ganglia (JNG), which in turn connect to pro-opiomelanocortinergic neurons in nucleus tractus solitarius (NTS), subsequently activating glutamatergic neurons in ventrolateral periaqueductal gray (vlPAG). Optogenetic stimulation of central vagus terminals, JNG-derived auricular peripheral fibers, or vlPAG-projecting NTS neurons mimics taVNS-induced analgesia, whereas chemogenetic silencing of central vagus terminals or NTS neurons abolishes this effect. This study identifies an auricle-to-brain circuit underlying taVNS-driven analgesia in mice, with potential for facilitating taVNS optimization for pain management and other neurological conditions.