Neural basis of transcutaneous electrical nerve stimulation for neuropathic pain relief

Existing treatments for chronic pain often prove ineffective and carry adverse side effects, highlighting the need for better analgesics, including non-pharmacological treatments. We demonstrate that transcutaneous electrical nerve stimulation (TENS), when repeatedly applied during the early phase of nerve injury in mice, produces sustained analgesic effects by activating the dorsal column nucleus (DCN)-thalamic-cortical pathway, which transmits vibration, discriminative touch, and proprioception. Mechanistically, TENS selectively activates glutamatergic neurons in the DCN (DCN^Glu) via exciting Aβ low-threshold mechanoreceptors (Aβ-LTMRs) in dorsal root ganglia (DRGs). These DCN^Glu neurons project to a distinct subset of glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPL^{DCN, Glu}), separate from neurons receiving spinal dorsal horn input (VPL^{SDH, Glu}). VPL^{DCN, Glu} neurons form monosynaptic connections with layer 5 neurons in the somatosensory hindlimb cortex (S1HL), mediating TENS-induced analgesia. Our findings disclosed a neural basis of TENS-mediated pain relief and offered a promising therapeutic target for neuropathic pain.