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

Admire Munanairi, Xian Yu Liu, Devin M. Barry, Qianyi Yang, Jun Bin Yin, Hua Jin, Hui Li, Qing Tao Meng, Jia Hang Peng, Zhen Yu Wu, Jun Yin, Xuan Yi Zhou, Li Wan, Ping Mo, Seungil Kim, Fu Quan Huo, Joseph Jeffry, Yun Qing Li, Rita Bardoni, Michael R. BruchasZhou Feng Chen

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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. Munanairi et al. show that the kappa opioid receptor (KOR) agonists inhibit nonhistaminergic itch transmission by attenuating the function of the gastrin-releasing peptide receptor (GRPR), an itch receptor in the spinal cord. KOR activation causes the translocation of PKCδ from plasma to membrane, which phosphorylates GRPR to dampen itch transmission.

Original languageEnglish
Pages (from-to)866-877
Number of pages12
JournalCell Reports
Issue number3
StatePublished - Apr 17 2018


  • GPCR cross-signaling
  • GRPR
  • KOR
  • PKC
  • itch
  • mouse
  • phosphorylation
  • spinal cord


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