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

Qian Zeng, Yitong Li, Yifei Wu, Jiawei Wu, Kangtai Xu, Yiming Chen, Yunfei Rao, Nan Li, Yuhui Luo, Changyu Jiang (), Chaoran Wu () and Zilong Wang ()
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Qian Zeng: 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

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62382-w

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