Abstract
It has been known that 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 Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.
Highlights
Pain and itch information is conveyed by distinct yet interacting neuronal pathways in sensory neurons and spinal cord to the brain[1,2,3,4,5,6]
To directly test whether gastrin releasing peptide receptor (GRPR) neurons are interneurons or projection neurons, we performed retrograde tracing of projection neurons by injecting the retrograde fluorescent tracer Fluoro-Gold (FG) into the thalamus or parabrachial nucleus (PBN) of GRPR-eGFP mice followed by double immunohistochemistry (IHC) staining as described (Fig. 1A–D,H–K)[30]
In this study, using classic neuroanatomical tracing and immuno-EM approach we demonstrate that GRPR neurons are excitatory interneurons that make contacts with neurokinin 1 receptor (NK1R) PBN- and spinothalamic track (STT)-projecting neurons, supporting earlier studies[13,14]
Summary
Pain and itch information is conveyed by distinct yet interacting neuronal pathways in sensory neurons and spinal cord to the brain[1,2,3,4,5,6]. It has been suggested that pain inhibits chemical itch through Dynorphin (Dyn) or Dyn-expressing GABAergic neurons, or BI-5 neurons, in the spinal cord[26]. Activation of neuropeptide Y 1 (NPY-Y1) has recently been shown to inhibit mechanical itch[28] and chemical itch[29]. Whether painful stimuli can activate NPY-Y1 remains unclear. We postulated that counter-stimuli inhibit itch by GABAergic signaling-mediated inhibition of GRPR function. Our studies reveal previously unknown features of GRPR neurons regarding their synaptic connectivity and inhibitory effects of counter-stimuli
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