Glutamatergic neurons in the nucleus accumbens represent a distinct functional population that gates pain

BACKGROUND: The nucleus accumbens (NAc) integrates affective and sensory information crucial for pain processing. While canonically viewed as a predominantly GABAergic structure, the potential existence and function of non-canonical excitatory populations remain poorly understood. We hypothesized that a distinct subpopulation of vesicular glutamate transporter 2 (VGluT2) neurons in the NAc exists and actively drives inflammatory pain and related anxiety behaviors. METHODS: In this controlled laboratory in vivo study using male mice, we identified and characterized NAc VGluT2 neurons using patch-clamp electrophysiology. A persistent inflammatory pain model was established via intraplantar complete Freund's adjuvant (CFA) injection. To determine functionality, we used viral-mediated chemogenetics to selectively inhibit these neurons. Main outcome measures included mechanical paw withdrawal frequency (PWF), thermal paw withdrawal latency (PWL), and pain-related anxiety evaluated via the open field test (OFT) and elevated plus maze (EPM). RESULTS: NAc VGluT2 neurons constitute a unique, non-GABAergic population, with >90% displaying intrinsic burst-firing. These neurons became significantly hyperexcitable under CFA-induced inflammatory pain conditions. Chemogenetic inhibition of NAc VGluT2 neurons successfully alleviated pain hypersensitivity. Furthermore, modulating this neuronal population bidirectionally regulated pain-related anxiety-like behaviors. CONCLUSIONS: VGluT2 neurons in the NAc represent a functionally distinct, burst-firing population that critically gates inflammatory pain and comorbid anxiety. Inhibiting this specific microcircuit provides a novel, precise target for treating persistent pain.