Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

• Early RET+ dDH neurons define a new population of DH inhibitory interneurons
• Early RET+ dDH neurons mediate crosstalk between touch and pain pathways
• Early RET+ dDH neurons inhibit DH transmission of both touch and pain pathways
• Early RET+ dDH neurons play critical roles in acute and chronic pain sensation

SummaryThe gate control theory (GCT) of pain proposes that pain- and touch-sensing neurons antagonize each other through spinal cord dorsal horn (DH) gating neurons. However, the exact neural circuits underlying the GCT remain largely elusive. Here, we identified a new population of deep layer DH (dDH) inhibitory interneurons that express the receptor tyrosine kinase Ret neonatally. These early RET+ dDH neurons receive excitatory as well as polysynaptic inhibitory inputs from touch- and/or pain-sensing afferents. In addition, they negatively regulate DH pain and touch pathways through both pre- and postsynaptic inhibition. Finally, specific ablation of early RET+ dDH neurons increases basal and chronic pain, whereas their acute activation reduces basal pain perception and relieves inflammatory and neuropathic pain. Taken together, our findings uncover a novel spinal circuit that mediates crosstalk between touch and pain pathways and suggest that some early RET+ dDH neurons could function as pain “gating” neurons.