2. Academic Validation
  3. Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord

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

  • Nat Commun. 2025 Aug 1;16(1):7074. doi: 10.1038/s41467-025-62382-w.
Qian Zeng # 1 2,  Yitong Li # 1,  Yifei Wu # 1,  Jiawei Wu 1,  Kangtai Xu 1,  Yiming Chen 1,  Yunfei Rao 1,  Nan Li 2,  Yuhui Luo 2,  Changyu Jiang 3,  Chaoran Wu 4,  Zilong Wang 5 6 7
Affiliations

Affiliations

  • 1 Department of Medical Neuroscience, School of Medicine; Shenzhen People's Hospital, The First Affiliated Hospital; Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 2 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, The 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, China.
  • 3 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, The 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, China. changyujiang@email.szu.edu.cn.
  • 4 Department of Medical Neuroscience, School of Medicine; Shenzhen People's Hospital, The First Affiliated Hospital; Southern University of Science and Technology, Shenzhen, Guangdong, China. wu.chaoran@szhospital.com.
  • 5 Department of Medical Neuroscience, School of Medicine; Shenzhen People's Hospital, The First Affiliated Hospital; Southern University of Science and Technology, Shenzhen, Guangdong, China. wangzl6@sustech.edu.cn.
  • 6 Key University Laboratory of Metabolism and Health of Guangdong School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China. wangzl6@sustech.edu.cn.
  • 7 SUSTech Homeostatic Medicine Institute, SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China. wangzl6@sustech.edu.cn.
  • # Contributed equally.
PMID: 40750771 DOI: 10.1038/s41467-025-62382-w
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.

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