Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord
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-indu...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62382-w |
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| Summary: | 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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| ISSN: | 2041-1723 |