biostudies-literatureSu XLeading Medicine and Advanced Technologies of IHMNational Natural Science Foundation of China74https://www.ebi.ac.uk/biostudies/studies/S-EPMC12487289biostudies-literatureUnknown18(1)Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGLUT3)-lineage sensory neurons may play a role in inhibiting itch, but the circuit mechanisms within the spinal cord remain unclear. In this study, we employed optogenetic techniques to activate VGLUT3-lineage sensory afferents in mice and observed a significant reduction in scratching behaviors elicited by both pruritogens and mechanical stimuli. Moreover, aversive component of chemical itch assessed by conditioned place aversion (CPA) was abrogated. Viral tracing combined with electrophysiological recordings revealed synaptic connections between VGLUT3⁺ sensory nMolecular brainIdentification of VGLUT3-expressing LTMRs-recruited spinal circuits for itch inhibition.PMC12487289322710482025IHM01100Liu XZhang YSu XWang LfalseIdentification of VGLUT3-expressing LTMRs-recruited spinal circuits for itch inhibition.Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGLUT3)-lineage sensory neurons may play a role in inhibiting itch, but the circuit mechanisms within the spinal cord remain unclear. In this study, we employed optogenetic techniques to activate VGLUT3-lineage sensory afferents in mice and observed a significant reduction in scratching behaviors elicited by both pruritogens and mechanical stimuli. Moreover, aversive component of chemical itch assessed by conditioned place aversion (CPA) was abrogated. Viral tracing combined with electrophysiological recordings revealed synaptic connections between VGLUT3⁺ sensory n2025-01-01T00:00:00Z2025 Sep2026-07-15T06:49:40.768Z2026-06-30T03:24:41.64ZS-EPMC124872894102977710.1186/s13041-025-01245-3