[PDF][PDF] How gastrin-releasing peptide opens the spinal gate for itch

M Pagani, GW Albisetti, N Sivakumar, H Wildner… - Neuron, 2019 - cell.com
M Pagani, GW Albisetti, N Sivakumar, H Wildner, M Santello, HC Johannssen, HU Zeilhofer
Neuron, 2019cell.com
Spinal 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 …
Summary
Spinal 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.
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