Downregulation of the NPY-Y1R system in Grpr neurons results in mechanical and chemical hyperknesis in chronic itch.

Chronic itch remains a clinically challenging condition with limited therapeutic efficacy, posing a significant burden on patients' quality of life. Despite its prevalence, the underlying neural mechanisms remain poorly understood. In this study, we explored the synaptic relationships between neuropeptide Y (NPY) neurons and gastrin-releasing peptide receptor (GRPR) neurons in the spinal cord. Our findings reveal a direct synaptic connection whereby Npy neurons provide inhibitory modulation to Grpr neurons. Notably, during chronic itch, the activity of Grpr neurons was significantly elevated, coinciding with a decrease in Y1 receptor expression and a reduction in both the frequency and amplitude of inhibitory postsynaptic currents (IPSCs). These results suggest a decline in NPY/Y1R system function during chronic itch, leading to a decreased inhibitory influence of Npy neurons on Grpr neurons and subsequent disinhibition and excitation of the latter. This disinhibitory mechanism may underlie the enhanced responsiveness to mechanical and chemical itch stimuli in chronic itch patients.