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.