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

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 G_αi 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.