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

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.