Parabrachial Npy1r ‐Expressing Neurons Drive Pain in a Mouse Model of Parkinson's Disease

BACKGROUND: Pain is a common and debilitating non-motor symptom of Parkinson's disease (PD), yet its underlying neural mechanisms remain poorly defined. OBJECTIVES: The aim was to test whether neuropeptide Y Y1 receptor (Npy1r)-expressing parabrachial neuronsdrive PD-associated pain. METHODS: In a unilateral 6 hydroxydopamine (6-OHDA) mouse model, pain-related behaviors, neuronal activation, and intrinsic excitability of parabrachial nucleus (PBN) neurons were assessed using behavioral assays, fluorescence in situ hybridization, and ex vivo whole-cell patch-clamp electrophysiology. Cell type-specific chemogenetic inhibition. RESULTS: Following 6-OHDA injection, mice developed robust multimodal hypersensitivity accompanied by increased recruitment of Npy1r-expressing PBN neurons. Chemogenetic silencing of Npy1r-expressing PBN neurons abolished PD-associated hypersensitivity, whereas activation induced pain-like behaviors in naïve mice. CONCLUSIONS: Npy1r-expressing PBNs are a discrete supraspinal population that drives pain in a preclinical model of PD.