NPY-Y2R driven neuroimmune signaling as a potential therapeutic target for trigeminal neuralgia: clinical and experimental evidence.

Trigeminal neuralgia (TN) is a debilitating orofacial pain disorder for which current treatments often provide incomplete or transient relief and do not address mechanisms that sustain chronic pain. Here, we identify neuropeptide Y (NPY) acting via the Y2 receptor (Y2R) as a previously unrecognized neuroimmune driver of TN and as a tractable therapeutic target. We prospectively enrolled 92 patients (TN and hemifacial spasm cohorts) and measured NPY concentrations in quality-controlled plasma and cerebrospinal fluid (CSF) samples (n = 40 per group for each biofluid) by ELISA. CSF, but not plasma, NPY was significantly elevated in TN patients and correlated with pain intensity, indicating that CSF NPY reflects compartmentalized trigeminal ganglion (TG) disease activity. Using a mouse model of partial infraorbital nerve transection (pT-ION), we show that injured TG neurons upregulated and released NPY. NPY acted on neighboring nociceptors via the Y2R, recruiting and activating TG macrophages, which released TNF-α and increased neuronal excitability, thereby establishing a self-amplifying neuron-macrophage feedback loop that sustained local neuroinflammation and mechanical allodynia. Pharmacological Y2R blockade (BIIE0246), genetic Npy2r deletion, or macrophage depletion each robustly reversed established allodynia. Together, these findings reveal NPY-Y2R as a mechanistic driver of TN, establish CSF NPY as a clinically relevant candidate biomarker for TN-associated pain, and highlight TG-directed Y2R as a promising strategy for mechanism-based therapy development.