Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

Abstract

A myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and A{delta} fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.\n\nHighlightsO_LIActivation of GRPR neurons evokes itch and is dependent upon NK1R activation\nC_LIO_LIGRPR neurons receive both direct and indirect inputs from C/A{delta} fibers\nC_LIO_LICounter-stimuli inhibit GRPR neurons via GABAergic signaling\nC_LIO_LIIncreased excitability of GRPR neurons in chronic itch condition\nC_LI