Spinal Mechanisms of Itch Transmission

Abstract

Peripheral itch stimuli are transmitted by sensory neurons to the spinal cord dorsal horn, which then transmits the information to the brain. The molecular and cellular mechanisms within the dorsal horn for itch transmission have only been investigated and identified during the past ten years. This review covers the progress that has been made in identifying the peptide families in sensory neurons and the receptor families in dorsal horn neurons as putative itch transmitters, with a focus on gastrin-releasing peptide (GRP)-GRP receptor signaling. Also discussed are the signaling mechanisms, including opioids, by which various types of itch are transmitted and modulated, as well as the many conflicting results arising from recent studies.

Keywords: DRG; GPCR signaling; Itch; Neuropeptides; Spinal cord.

Fig. 1

Expression of putative itch peptides in dorsal root ganglia. Left, expression of gastrin-releasing peptide (Grp) mRNA by in situ hybridization (ISH). Left center, staining of GRP by immunohistochemistry (IHC). Right center, neuromedin B (Nmb) mRNA expression by ISH. Right, expression of natriuretic peptide B (Nppb) mRNA that encodes brain natriuretic peptide by ISH. Images from the Chen laboratory.

Fig. 2

Cross-signaling between G_αi-coupled GPCRs and G_αq-coupled GRPR stimulates Ca²⁺ signaling. Left, upon its activation by morphine, MOR1D cross-activates GRPR, stimulating signal propagation. Right, co-activation of 5-HT1A and GRPR receptors by 5-HT andGRP stimulates PLCβ/Ca²⁺ signaling and itch propagation. DAG, diacyl glycerol; ER, endoplasmic reticulum; IP₃, inositol trisphosphate; IP₃R, IP₃ receptor; PIP₂, phosphatidylinositol 4,5-bisphosphate; SERCA, sarco/endoplasmic reticulum Ca²⁺ ATPase.

Fig. 3

Expression of itch peptide and receptor mRNA in spinal dorsal horn. Left, detection of Grp by ISH from (upper panel) Allen Institute for Brain Science [61] and (lower panel) the Chen laboratory. Center, detection of Npr1 by ISH from (upper) Allen Institute for Brain Science and (lower) the Chen laboratory. Right, expression of Grpr by ISH from the Chen laboratory.

Fig. 4

Model for itch transmission by GRP-GRPRs and NMB-NMBRs from periphery to spinal dorsal horn. Non-histaminergic itch is transmitted, in part, by GRP from the DRG to GRPR⁺ neurons in the dorsal horn. The role of NMB/NMBR signaling in the spinal cord and DRG for itch/pain remains unresolved. GRPR⁺ neurons act as a convergence point for transmitting itch information from the periphery to the brain via spinal projection neurons.