Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice

Cell Rep. 2018 Apr 17;23(3):866-877. doi: 10.1016/j.celrep.2018.03.087.

Abstract

Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated Gαi signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca2+-independent protein kinase C (PKC)δ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies.

Keywords: GPCR cross-signaling; GRPR; KOR; PKC; itch; mouse; phosphorylation; spinal cord.

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Chloroquine / toxicity
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism
  • Pruritus / chemically induced
  • Pruritus / pathology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Bombesin / metabolism
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / deficiency
  • Receptors, Opioid, kappa / genetics*
  • Signal Transduction*
  • Spinal Cord / metabolism*
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism

Substances

  • RNA, Small Interfering
  • Receptors, Bombesin
  • Receptors, Opioid, kappa
  • Chloroquine
  • Prkcd protein, mouse
  • Protein Kinase C-delta
  • Type C Phospholipases
  • GTP-Binding Protein alpha Subunits, Gi-Go