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. Bruchas,
Zhou-Feng Chen
Affiliations
Admire Munanairi
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Xian-Yu Liu
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Devin M. Barry
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Qianyi Yang
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Jun-Bin Yin
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC
Hua Jin
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA
Hui Li
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC
Qing-Tao Meng
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Jia-Hang Peng
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Zhen-Yu Wu
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC
Jun Yin
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Xuan-Yi Zhou
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA
Li Wan
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC
Ping Mo
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC
Seungil Kim
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA
Fu-Quan Huo
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA
Joseph Jeffry
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yun-Qing Li
Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, 710032 Xi’an, PRC; Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, PRC
Rita Bardoni
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy
Michael R. Bruchas
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
Zhou-Feng Chen
Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: 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. Keywords: KOR, GRPR, itch, PKC, phosphorylation, GPCR cross-signaling, spinal cord, mouse
