Abstract

SummarySpinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.

Highlights

  • The senses of pain and itch have evolved to protect organisms from potentially harmful agents and stimuli (Yosipovitch et al, 2007)

  • Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between gastrin-releasing peptide (GRP) and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation

  • When we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons

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Summary

Introduction

The senses of pain and itch have evolved to protect organisms from potentially harmful agents and stimuli (Yosipovitch et al, 2007). While the exposure to acute painful stimuli typically evokes an almost immediate withdrawal reflex and a fast onset pain sensation, pruritogens elicit a more prolonged ‘‘waxing and waning’’ sensation (Forster and Handwerker, 2014) and a less precisely timed scratching response aimed at the removal of the irritant Reponses to both types of stimuli are initiated by the activation of different types of specialized sensory nerve fibers, called nociceptors and pruritoceptors, which convey sensory information to the spinal or medullary dorsal horn. Several neuropeptides are expressed by peripheral pruritoceptors, including B-type natriuretic peptide (Huang et al, 2018; Mishra and Hoon, 2013) and neuromedin B (Goswami et al, 2014; Wan et al, 2017) These are likely released in the spinal cord, but it is at present unclear whether they are required for efficient itch relay to central (spinal cord) neurons. The currently prevailing concept of spinal pruritoceptive signal transmission suggests that secondorder dorsal horn interneurons that are activated by peripheral pruritoceptive neurons release GRP and in turn excite third-order (GRPR) interneurons that transmit pruritoceptive signals to spinoparabrachial (fourth-order) projection neurons (Goswami et al, 2014; Huang et al, 2018; Mu et al, 2017)

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