Parabrachial neuropeptide Y Y1 receptor-expressing neurons govern the sensory dimension of neuropathic pain.

Pain perception involves complex sensory and emotional processes, yet the supraspinal circuits that sustain neuropathic pain remain incompletely understood. Here, we demonstrate that parabrachial nucleus (PBN) neurons expressing the inhibitory G-protein-coupled neuropeptide Y Y1 receptor (Npy1r) are critical modulators of neuropathic pain. Approximately 19% of lateral PBN neurons express Npy1r. Stimulus-evoked Fos activation and calcium dynamics of these neurons increases in mice with spared nerve injury (SNI) compared to sham controls. Pharmacological activation of Y1 receptors or chemogenetic inhibition of Npy1r neurons attenuates SNI-induced mechanical and cold allodynia, without altering baseline sensitivity or conditioned place preference (a measure of affective pain). Preemptive ablation of parabrachial Npy1r neurons before SNI delayed the development of neuropathic hypersensitivity. Conversely, repeated chemogenetic activation of Npy1r neurons produced persistent mechanical and cold hypersensitivity in uninjured animals; this outlasted neuronal activation, indicating sufficiency to drive pain-like states. Viral tracing revealed dense Npy1r projections from lateral parabrachial neurons to forebrain regions including the central amygdala, lateral hypothalamus, zona incerta, and ventromedial thalamus, sites implicated in the sensory and affective dimension of pain. These findings demonstrate that Npy1r-expressing PBN neurons selectively regulate the sensory-discriminative component of neuropathic pain and can maintain long-lasting hypersensitivity even in the absence of injury.