Spinal and supraspinal mechanisms of chronic itch: from neuronal circuits to the neuro-immune-microbial axis

Itch is an unpleasant sensation that evokes scratching behavior; when it becomes chronic, it severely impairs quality of life, and current therapies have limited efficacy against non-histaminergic itch. The spinal cord serves as a key hub for itch integration, mediating chemical and mechanical itch through distinct neuronal subpopulations such as gastrin-releasing peptide (GRP) and its receptor (GRPR⁺), neuropeptide Y1 receptor (NPY1R⁺), and urocortin 3 (UCN³⁺) neurons, and is also regulated by inhibitory microcircuits and glial cells. Recent studies have shown that remodeling of spinal itch circuits depends not only on local neurons and glial cells but also on remote regulation by systemic signals, including peripheral immunity and the "gut-spinal cord axis," forming a multi-level neuro-immune-microbial network. Meanwhile, chronic inflammation can amplify or convert itch signals even before they enter the spinal cord by reshaping peripheral-spinal pathways, altering immune cell functions, and modulating epithelial-neural interactions. At supraspinal levels, the ventral tegmental area (VTA)-nucleus accumbens (NAc) reward circuit encodes the pleasure and motivation associated with scratching, driving the "itch-scratch" cycle. Descending regulatory pathways constitute an important anti-itch system: Tac1⁺ glutamatergic neurons in the periaqueductal gray promote scratching, whereas the cortex (rostral anterior cingulate cortex [rACC]) activates periaqueductal gray GABAergic neurons through excitatory projections; these, in turn, descend via the rostral ventromedial medulla to the spinal cord, directly or indirectly inhibiting GRPR⁺ itch-transmitting neurons. Multiple neuronal subpopulations in the rostral ventromedial medulla, including neurokinin 1 receptor (NK1R⁺), κ-opioid receptor⁺ (KOR), and GPER⁺ neurons, participate in itch suppression. In addition, A11 dopaminergic neurons project descending fibers to the spinal cord and facilitate itch transmission via the DRD1⁺-GRP-GRPR microcircuit, together with the midbrain reward circuit constituting a dual dopaminergic modulation of itch. These findings extend itch regulation from local spinal circuits to a whole-brain-spinal-body network encompassing peripheral immunity, ascending reward, and descending inhibition. In-depth elucidation of itch-pain interactions, the functions of opioid receptor subtypes, and the specific pathways underlying mechanical itch is expected to facilitate translational application of targeted therapies, providing precise and effective intervention strategies for refractory chronic itch.