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Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord

Author

Listed:
  • Qian Zeng

    (Shenzhen
    Shenzhen)

  • Yitong Li

    (Shenzhen)

  • Yifei Wu

    (Shenzhen)

  • Jiawei Wu

    (Shenzhen)

  • Kangtai Xu

    (Shenzhen)

  • Yiming Chen

    (Shenzhen)

  • Yunfei Rao

    (Shenzhen)

  • Nan Li

    (Shenzhen)

  • Yuhui Luo

    (Shenzhen)

  • Changyu Jiang

    (Shenzhen)

  • Chaoran Wu

    (Shenzhen)

  • Zilong Wang

    (Shenzhen
    Shenzhen
    Shenzhen)

Abstract

Itch is a common side effect of opioid analgesics. The specific neurons mediating opioid-induced itch are still debated, and the mechanistic neuronal circuits remain elusive. Here, we show that the μ-opioid receptors (MOR) on neuropeptide Y (NPY)+ inhibitory interneurons mediate opioid-induced itch at the spinal cord level in mice. The MOR gene Oprm1 is expressed in NPY+ neurons in the spinal dorsal horn, and specific deletion of Oprm1 in NPY+ interneurons abolishes intrathecal morphine-induced itch. Furthermore, gastrin-releasing peptide (GRP)+ neurons are the direct downstream targets of NPY+ neurons. Mechanistically, morphine inhibits the neuronal excitability of NPY+ interneurons and reduces inhibitory synaptic inputs on GRP+ neurons, causing disinhibition of GRP+ neurons and further activation of gastrin-releasing peptide receptor (GRPR)+ neurons. The NPY/neuropeptide Y receptor 1(NPY1R) system is essential for regulating GRP+ neurons in opioid-induced itch. These findings reveal that intrathecal opioids act on MOR on NPY+ inhibitory neurons in the spinal dorsal horn, which subsequently disinhibit GRP-GRPR microcircuits, triggering the itch response.

Suggested Citation

  • Qian Zeng & Yitong Li & Yifei Wu & Jiawei Wu & Kangtai Xu & Yiming Chen & Yunfei Rao & Nan Li & Yuhui Luo & Changyu Jiang & Chaoran Wu & Zilong Wang, 2025. "Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62382-w
    DOI: 10.1038/s41467-025-62382-w
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    References listed on IDEAS

    as
    1. Xiao-Jun Chen & Yan-Gang Sun, 2020. "Central circuit mechanisms of itch," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Yan-Gang Sun & Zhou-Feng Chen, 2007. "A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord," Nature, Nature, vol. 448(7154), pages 700-703, August.
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