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Itch serves as a self-protection mechanism against harmful external agents, whereas uncontrolled and persistent itch severely influences the quality of life of patients and aggravates their diseases. Unfortunately, the existing treatments are largely ineffective. The current difficulty in treatment may be closely related to the fact that the central neural mechanisms underlying itch processing, especially descending inhibition of itch, are poorly understood. Here, we demonstrate that an excitatory descending neural circuit from rostral anterior cingulate cortex pyramidal (rACC Py ) neurons to periaqueductal gray GABAergic (PAG GABA ) neurons plays a key role in the inhibition of itch. The activity of itch-tagged rACC Py neurons decreases during the itch-evoked scratching period. Artificial activation or inhibition of the neural circuits significantly impairs or enhances itch processing, respectively. Thus, an excitatory neural circuit is identified as playing a crucial inhibitory role in descending regulation of itch, suggesting that it could be a potential target for treating itch., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)